Cyanamide, alkoxyamino, and urea derivatives of 1,3-benzodiazephine as HIV reverse transcriptase inhibitors

ABSTRACT

The present invention relates to 1,3-benzodiazepin-2-ones and 1,3-benzoxazepin-2-ones of formula I:  
                 
 
     or stereoisomeric forms, stereoisomeric mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as an assay standard or reagent.

FIELD OF THE INVENTION

[0001] This invention relates generally to cyanamide, hydroxyamino, and nitroolefin derivatives of 1,3-benzodiazapines which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as assay standards or reagents, and intermediates and processes for making the same.

BACKGROUND OF THE INVENTION

[0002] Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.

[0003] The disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle. The virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion's protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell's genes and those genes are used for virus reproduction.

[0004] At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle's maturing into a virus that is capable of full infectivity.

[0005] The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system's T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system's effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body's immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators, or both, death may result.

[0006] There are at least three critical points in the virus's life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.

[0007] Inhibition of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treading AIDS. This transcription must occur for the virion to reproduce because the virion's genes are encoded in RNA and the host cell reads only DNA. By introducing drugs that block the reverse transcriptase from completing the formation of viral DNA, HIV-1 replication can be stopped.

[0008] A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxycytidine (ddC), 2′,3′-dideoxythymidinene (d4T), 2′,3′-dideoxyinosine (ddI), and 2′,3′-dideoxy-3′-thia-cytidine (3TC) have been shown to be relatively effective in halting HIV replication at the reverse transcriptase (RT) stage.

[0009] An active area of research is in the discovery of non-nucleoside HIV reverse transcriptase inhibitors. As an example, it has been found that certain benzoxazinones and quinazolinones are active in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS.

[0010] U.S. Pat. No. 5,519,021 describe reverse transcriptase inhibitors which are benzoxazinones of the formula:

[0011] wherein X is a halogen, Z may be O.

[0012] EP 0,530,994 and WO 93/04047 describe HIV reverse transcriptase inhibitors which are quinazolinones of the formula A:

[0013] wherein G is a variety of groups, R³ and R⁴ may be H, Z may be O, R² may be unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycle, and optionally substituted aryl, and R¹ may be a variety of groups including substituted alkyl.

[0014] WO 95/12583 also describes HIV reverse transcriptase inhibitors of formula A. In this publication, G is a variety of groups, R³ and R⁴ may be H, Z may be O, R² is substituted alkenyl or substituted alkynyl, and R¹ is cycloalkyl, alkynyl, alkenyl, or cyano. WO 95/13273 illustrates the asymmetric synthesis of one of the compounds of WO 95/12583, (S)-(−)-6-chloro-4-cyclopropyl-3,4-dihydro-4((2-pyridy)ethynyl)-2(1H)-quinazolinone.

[0015] Synthetic procedures for making quinazolinones like those described above are detailed in the following references: Houpis et al, Tetr. Lett. 1994, 35(37), 6811-6814; Tucker et al, J. Med. Chem. 1994, 37, 2437-2444; and, Huffman et al, J. Org. Chem. 1995, 60, 1590-1594.

[0016] DE 4,320,347 illustrates quinazolinones of the formula:

[0017] wherein R is a phenyl, carbocyclic ring, or a heterocyclic ring. Compounds of this sort are not considered to be part of the present invention.

[0018] WO 00/00479 discloses 1,3-benzodiazapines of the formula:

[0019] wherein A is O or S. Compounds of this type are not considered part of the present invention.

[0020] Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a single inhibitor. Thus, it is desirable to develop additional inhibitors to further combat HIV infection.

SUMMARY OF THE INVENTION

[0021] Accordingly, one aspect of the present invention is to provide novel reverse transcriptase inhibitors.

[0022] The present invention further provides a novel method of treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

[0023] The present invention provides a novel method of treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

[0024] The present invention provides pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

[0025] The present invention provides a method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention.

[0026] The present invention provides a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

[0027] The present invention provides novel compounds for use in therapy.

[0028] The present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of HIV.

[0029] These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I):

[0030] wherein R¹, R², R⁸, W, X, Y, Z, and A are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0031] [1] Thus, in an embodiment, the present invention provides a novel compound of formula I:

[0032] or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

[0033] A is N—CN, N—CONH₂, or N—OR¹¹;

[0034] W is N or CR³;

[0035] X is N or CR^(3a);

[0036] Y is N or CR^(3b);

[0037] Z is N or CR^(3c);

[0038] provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

[0039] R¹ is selected from the group C₁₋₃ alkyl substituted with 0-7 halogen and cyclopropyl;

[0040] R² is selected from the group —R^(2c), —OR^(2c), —OCHR^(2a)R^(2b), —OCH₂CHR^(2a)R^(2b), —O(CH₂)₂CHR^(2a)R^(2b), —OCHR^(2a)C═C—R^(2b), —OCHR^(2a)C═R^(2c), —OCHR^(2a)C═C—R^(2b), —SR^(2c), —SCHR^(2a)R^(2b), —SCH₂CHR^(2a)R^(2b), —S(CH₂)₂CHR^(2a)R^(2b), —SCHR^(2a)C═C—R^(2b), —SCHR^(2a)C═R^(2c), —SCHR^(2a)C═C—R^(2b), —NR^(2a)R^(2c), —NHCHR^(2a)R^(2b), —NHCH₂CHR^(2a)R^(2b), —NH(CH₂)₂CHR^(2a)R^(2b), —NHCHR^(2a)C═C—R^(2b), —NHCHR^(2a)C═R^(2c), and NHOHR^(2a)C═C—R^(2b);

[0041] R^(2a) is selected from the group H, CH₃, CH₂CH₃, CH(CH₃)₂, and CH₂CH₂CH₃;

[0042] R^(2b) is H or R^(2c);

[0043] R^(2c) is selected from the group C₁₋₆ alkyl substituted with 0-2 R⁴, C₂₋₅ alkenyl substituted with 0-2 R⁴, C₂₋₅ alkynyl substituted with 0-1 R⁴, C₃₋₆ cycloalkyl substituted with 0-2 R^(3d), phenyl substituted with 0-2 R^(3d), and 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R^(3d);

[0044] alternatively, the group —NR^(2a)R^(2c) represents a 4-7 membered cyclic amine, wherein 0-1 carbon atoms are replaced by O or NR⁵;

[0045] R³ is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, —SO₂NR⁵R^(5a), and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S;

[0046] R^(3a) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, —SO₂NR⁵R^(5a), and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S;

[0047] alternatively, R³ and R^(3a) together form —OCH₂O—;

[0048] R^(3b) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a);

[0049] alternatively, R^(3a) and R^(3b) together form —OCH₂O—;

[0050] R^(3c) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a);

[0051] alternatively, R^(3b) and R^(3c) together form —OCH₂O—;

[0052] R^(3d), at each occurrence, is independently selected from the group C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a);

[0053] R^(3e), at each occurrence, is independently selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a);

[0054] R^(3f), at each occurrence, is independently selected from the group C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a);

[0055] R^(3g), at each occurrence, is independently selected from the group C₁₋₄ alkyl, C₂₋₅ alkenyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, —SO₂NR⁵R^(5a), C₃₋₁₀ carbocycle substituted with 0-3 R^(3f) and a 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-3 R^(3f); and,

[0056] R⁴ is selected from the group F, Cl, Br, I, C₁₋₆ alkyl substituted with 0-2 R^(3e), C₃₋₁₀ carbocycle substituted with 0-2 R^(3e), phenyl substituted with 0-5 R^(3e), and a 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R^(3e);

[0057] R⁵ and R^(5a) at each occurrence are independently selected from the group H and C₁₋₄ alkyl;

[0058] alternatively, R⁵ and R^(5a), together with the nitrogen to which they are attached, combine to form a 5-6 membered ring containing 0-1 O or N atoms;

[0059] R⁶ is selected from the group H, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, and NR⁵R^(5a);

[0060] R⁷ is selected from the group C₁₋₃ alkyl and C₁₋₃ alkoxy;

[0061] R⁸ is selected from the group H, OR⁹, SR⁹, NR⁵R⁹, C₁₋₆ alkyl substituted with 0-3 R^(3g), C₂₋₆ alkenyl substituted with 0-3 R^(3g), C₂₋₆ alkynyl substituted with 0-3 R^(3g), C₃₋₅ cycloalkyl substituted with 0-2 R^(3f), phenyl substituted with 0-5 R^(3f), and a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R^(3f);

[0062] R⁹ is selected from the group C₃₋₁₀ carbocycle substituted with 0-5 R^(3f) and a 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R^(3f);

[0063] R¹⁰ is selected from the group C₁₋₄ alkyl and phenyl; and

[0064] R¹¹ is selected from the group H and C₁₋₄ alkyl.

[0065] [2] In a preferred embodiment, the present invention provides a novel compound of formula I, wherein:

[0066] R¹ is selected from the group C₁₋₃ alkyl substituted with 1-7 halogen and cyclopropyl;

[0067] R² is selected from the group —R^(2c), —OR^(2c), —OCHR^(2a)R^(2b), —OCH₂CHR^(2a)R^(2b), —O(CH₂)₂CHR^(2a)R^(2b), —OCHR^(2a)C═C—R^(2b), —OCHR^(2a)C═R^(2c), —OCHR^(2a)C≡C—R^(2b), —SR^(2c), —SCHR^(2a)R^(2b), —SCH₂CHR^(2a)R^(2b), —S(CH₂)₂CHR^(2a)R^(2b), —SCHR^(2a)C═C—R^(2b), —SCHR^(2a)C═R^(2c), and —SCHR^(2a)C≡C—R^(2b);

[0068] R^(2a) is selected from the group H, CH₃, CH₂CH₃, CH(CH₃)₂, and CH₂CH₂CH₃;

[0069] R^(2b) is H or R^(2c);

[0070] R^(2c) is selected from the group C₁₋₅ alkyl substituted with 0-2 R⁴, C₂₋₅ alkenyl substituted with 0-2 R⁴, C₂₋₅ alkynyl substituted with 0-1 R⁴, C₃₋₆ cycloalkyl substituted with 0-2 R^(3d), and phenyl substituted with 0-2 R^(3d);

[0071] R³, at each occurrence, is independently selected from the group H, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, NHC(O)NR⁵R^(5a), and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S;

[0072] R^(3a), at each occurrence, is independently selected from the group H, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, NHC(O)NR⁵R^(5a), and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S;

[0073] alternatively, R³ and R^(3a) together form —OCH₂O—;

[0074] R^(3b), at each occurrence, is independently selected from the group H, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a);

[0075] alternatively, R^(3a) and R^(3b) together form —OCH₂O—;

[0076] R⁴ is selected from the group Cl, F, C₁₋₄ alkyl substituted with 0-2 R^(3e), C₃₋₅ carbocycle substituted with 0-2 R^(3e), phenyl substituted with 0-5 R^(3e), and a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R^(3e);

[0077] R⁵ and R^(5a) are independently selected from the group H, CH₃ and C₂H₅;

[0078] R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a);

[0079] R⁷ is selected from the group CH₃, C₂H₅, CH(CH₃)₂, OCH₃, OC₂H₅, and OCH(CH₃)₂; and,

[0080] R⁸ is selected from the group H, cyclopropyl, CH₃, C₂H₅, and CH(CH₃)₂.

[0081] [3] In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

[0082] R¹ is selected from the group CF₃, C₂F₅, and cyclopropyl;

[0083] R² is selected from the group —R^(2c), —OR^(2c), —OCHR^(2a)R^(2b), —OCH₂CHR^(2a)R^(2b), —OCHR^(2a)C═C—R^(2b), —OCHR^(2a)C═R^(2c), —OCHR^(2a)C≡C—R^(2b), —SR^(2c), —SCHR^(2a)R^(2b), —SCH₂CHR^(2a)R^(2b), —SCHR^(2a)C═C—R^(2b), —SCHR^(2a)C═R^(2c), and —SCHR^(2a)C≡C—R^(2b);

[0084] R^(2a) is selected from the group H, CH₃, CH₂CH₃, CH(CH₃)₂, and CH₂CH₂CH₃;

[0085] R^(2b) is H or R^(2c);

[0086] R^(2c) is selected from the group C₁₋₃ alkyl substituted with 0-2 R⁴, C₂₋₃ alkenyl substituted with 0-2 R⁴, C₂₋₃ alkynyl substituted with 0-1 R⁴, and C₃₋₆ cycloalkyl substituted with 0-2 R^(3d);

[0087] R³, at each occurrence, is independently selected from the group H, C₁₋₃ alkyl, OH, C₁₋₃ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a);

[0088] alternatively, R³ and R^(3a) together form —OCH₂O—;

[0089] R^(3b) is H;

[0090] R^(3c) is H;

[0091] R^(3e), at each occurrence, is independently selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, —NR⁵R^(5a), —C(O)R⁶, and —SO₂NR⁵R^(5a);

[0092] R⁴ is selected from the group Cl, F, C₁₋₄ alkyl substituted with 0-1 R^(3e), C₃₋₅ carbocycle substituted with 0-2 R^(3e), phenyl substituted with 0-2 R^(3e), and a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R^(3e);

[0093] R⁵ and R^(5a) are independently selected from the group H, CH₃ and C₂H₅;

[0094] R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a);

[0095] R⁷ is selected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅; and,

[0096] R⁸ is selected from the group H, cyclopropyl, CH₃, and C₂H₅.

[0097] [4] In an even more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

[0098] R¹ is CF₃;

[0099] R² is selected from the group —R^(2c), —OR^(2c), —OCH₂R^(2b), —OCH₂CH₂R^(2b), —OCH₂C═C—R^(2b), —OCH₂C≡C—R^(2b), —SR^(2c), —SCH₂R^(2b), —SCH₂CH₂R^(2b), —SCH₂C═C—R^(2b), and —SCH₂C≡C—R^(2b);

[0100] R^(2b) is H or R^(2c);

[0101] R^(2c) is selected from the group methyl substituted with 0-2 R⁴, ethyl substituted with 0-2 R⁴, propyl substituted with 0-2 R⁴, ethenyl substituted with 0-2 R⁴, 1-propenyl substituted with 0-2 R⁴, 2-propenyl substituted with 0-2 R⁴, ethynyl substituted with 0-2 R⁴, 1-propynyl substituted with 0-2 R⁴, 2-propynyl substituted with 0-2 R⁴, and cyclopropyl substituted with 0-1 R^(3d);

[0102] R³, at each occurrence, is independently selected from the group H, C₁₋₃ alkyl, OH, C₁₋₃ alkoxy, F, Cl, NR⁵R^(5a), NO₂, —CN, and C(O)R⁶;

[0103] alternatively, R³ and R^(3a) together form —OCH₂O—;

[0104] R^(3d), at each occurrence, is independently selected from the group CH₃, —OH, OCH₃, OCF₃, F, Cl, and —NR⁵R^(5a);

[0105] R^(3e), at each occurrence, is independently selected from the group CH₃, —OH, OCH₃, OCF₃, F, Cl, and —NR⁵R^(5a);

[0106] R⁴ is selected from the group Cl, F, CH₃, CH₂CH₃, cyclopropyl substituted with 0-1 R^(3e), 1-methyl-cyclopropyl substituted with 0-1 R^(3e), cyclobutyl substituted with 0-1 R^(3e), phenyl substituted with 0-2 R^(3e), and a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R^(3e), wherein the heterocyclic group is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, and 2-imidazolyl;

[0107] R⁵ and R^(5a) are independently selected from the group H, CH₃ and C₂H₅;

[0108] R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a);

[0109] R⁷ is selected from the group CH₃, C₂H₅, OCH₃, and OC₂H_(5;) and,

[0110] R⁸ is selected from the group H, cyclopropyl, and C₂H₅.

[0111] [5] In a further preferred embodiment, wherein the compound is of formula Ia

[0112] [6] In a further preferred embodiment, wherein the compound is of formula Ib:

[0113] [7] In a further preferred embodiment, the compound of formula I is selected from the group:

[0114] 7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine;

[0115] 7-chloro-2-cyanoimino-5-(cyclobutylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine;

[0116] 7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-3-ethyl-5-trifluoromethyl-1,3-benzodiazepine;

[0117] 7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine;

[0118] 7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-3-ethyl-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine;

[0119] or a pharmaceutically acceptable salt form thereof.

[0120] [8] In another further preferred embodiment, the compound of formula I is selected from the group:

[0121] (S)-7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine;

[0122] (S)-7-chloro-2-cyanoimino-5-(cyclobutylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine;

[0123] (S)-7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-3-ethyl-5-trifluoromethyl-1,3-benzodiazepine;

[0124] (S)-7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine;

[0125] (S)-7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-3-ethyl-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine;

[0126] or a pharmaceutically acceptable salt form thereof.

[0127] [9] In another further preferred embodiment, the compound of formula I is selected from the group:

[0128] (R)-7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine;

[0129] (R)-7-chloro-2-cyanoimino-5-(cyclobutylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine;

[0130] (R)-7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-3-ethyl-5-trifluoromethyl-1,3-benzodiazepine;

[0131] (R)-7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine;

[0132] (R)-7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-3-ethyl-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine;

[0133] or a pharmaceutically acceptable salt form thereof.

[0134] In another embodiment, the present invention provides compounds of formula I wherein R¹ is CF₃.

[0135] In another embodiment, the present invention provides compounds of formula I wherein R² is OR^(2c); R^(2c) is methyl substituted with 0-2 R⁴; and R⁴ is selected from cyclopropyl and cyclobutyl.

[0136] In another embodiment, the present invention provides compounds of formula I wherein A is C—CN.

[0137] In another embodiment, the present invention provides compounds of formula I wherein A is N—CONH₂.

[0138] In another embodiment, the present invention provides compounds of formula I wherein A is N—OR¹¹; and R¹¹ is selected from H, methyl, ethyl, propyl, i-propyl and butyl.

[0139] In another embodiment, the present invention provides compounds of formula I wherein W is CR³; X is CR^(3a); Y is CR^(3b); and Z is CR^(3c).

[0140] In another embodiment, the present invention provides compounds of formula I wherein R³, R^(3b), and R^(3c) are H; and R^(3a) is selected from H, Cl, F, and Br.

[0141] In another embodiment, the present invention provides compounds of formula I wherein R⁸ is selected from H, methyl, ethyl, and propyl.

[0142] In another embodiment, the present invention provides compounds of formula I wherein R⁸ is H.

[0143] In another embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.

[0144] In another embodiment, the present invention provides a novel method of treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.

[0145] In another embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:

[0146] (a) a compound of formula I; and,

[0147] (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

[0148] In another preferred embodiment, the reverse transcriptase inhibitor is selected from the group AZT, ddC, ddI, d4T, 3TC, DPC082, DPC083, DPC961, DPC963, AG1549 delavirdine, efavirenz, nevirapine, Ro 18,893, trovirdine, MKC-442, HBY 097, ACT, UC-781, UC-782, RD4-2025, and MEN 10979, and the protease inhibitor is selected from the group saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, palinavir, BMS-232623, GS3333, KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, and ABT-378.

[0149] In an even more preferred embodiment, the reverse transcriptase inhibitor is selected from the group AZT, efavirenz, and 3TC and the protease inhibitor is selected from the group saquinavir, ritonavir, nelfinavir, and indinavir.

[0150] In a still further preferred ebodiment, the reverse transcriptase inhibitor is AZT.

[0151] In another still further preferred embodiment, the protease inhibitor is indinavir.

[0152] In another embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:

[0153] (a) a compound of formula I or a pharmaceutically acceptable salt form thereof; and,

[0154] (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.

[0155] In another embodiment, the present invention provides novel compounds of formula I or pharmaceutically acceptable salt forms thereof for use in therapy.

[0156] In another embodiment, the present invention provides the use of novel compounds of formula I or pharmaceutically acceptable salt forms thereof for the manufacture of a medicament for the treatment of HIV.

[0157] The invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention also encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional even more preferred embodiments of the present invention. Furthermore, any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.

[0158] Definitions

[0159] The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Geometric isomers of double bonds such as olefins and C═N double bonds can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.

[0160] The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring.

[0161] The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0162] When any variable (e.g., R⁶) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R⁶, then said group may optionally be substituted with up to two R⁶ groups and R⁶ at each occurrence is selected independently from the definition of R⁶. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0163] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0164] As used herein, “alkyl” or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C₁₋₆ alkyl (or alkylene), is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C₁₋₁₀ alkoxy, is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C₃₋₁₀ cycloalkyl, is intended to include C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ cycloalkyl groups. “Alkenyl” or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C₂₋₆ alkenyl (or alkenylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. “Alkynyl” or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C₂₋₆ alkynyl (or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynyl groups.

[0165] “Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and “counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.

[0166] As used herein, “carbocycle” or “carbocyclic group” is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

[0167] As used herein, the term “heterocycle” or “heterocyclic group” is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term “aromatic heterocyclic group” or “heteroaryl” is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.

[0168] Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benztriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

[0169] As used herein, “HIV reverse transcriptase inhibitor” is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Also included is Glaxo's combination of AZT and 3TC. Examples of non-nucleoside RT inhibitors include, but are no limited to, DPC082 (Bristol-Myers Squibb), (+)-4-Cyclopropylethenyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone), DPC083 (Bristol-Myers Squibb), (−)-6-chloro-4-E-cyclopropylethenyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone), DPC₉₆₁ (Bristol-Myers Squibb), (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone), DPC₉₆₃ (Bristol-Myers Squibb), (+)-4—Cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone), AG1549 (Warner Lambert/Shionogi), delavirdine (Pharmacia and Upjohn U90152S), efavirenz (Bristol-Myers Squibb), nevirapine (Boehringer Ingelheim), Ro 18,893 (Roche), trovirdine (Lilly), MKC-442 (Triangle), HBY 097 (Hoechst), ACT (Korean Research Institute), UC-781 (Rega Institute), UC-782 (Rega Institute), RD4-2025 (Tosoh Co. Ltd.), and MEN 10979 (Menarini Farmaceutici).

[0170] As used herein, “HIV protease inhibitor” is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), VX-478 (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), KNI-272 (Japan Energy), CGP-61755 (Ciba-Geigy), U-140690 (Pharmacia and Upjohn), and ABT-378. Additional examples include the cyclic protease inhibitors disclosed in WO93/07128, WO 94/19329, WO 94/22840, and PCT Application Number U.S. Pat. Ser. No. 96/03426.

[0171] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0172] As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.

[0173] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

[0174] Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. “Prodrugs” are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and acetamide, formamide, and benzamide derivatives of amine functional groups in the compounds of the present invention.

[0175] “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contempleted by the present invention.

[0176] “Therapeutically effective amount” is intended to include an amount of a compound of the present invention alone or in combination with other active ingredients or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.

[0177] As used herein, “treating” or “treatment” cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.

[0178] Synthesis

[0179] The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference. In the Schemes which follow, R¹ is shown as a CF₃ group, but could be any one of the presently described R¹ groups.

[0180] A method for preparing compounds of the present invention, N-cyanoguanadines or N-amidoguanadines, is shown in Scheme 1. A trifluoromethyl ketone 1 is treated with dimethylsulfoxonium methylide, dimethylsulfonium methylide, or diazomethane to give an epoxide 2 which is then reacted with ammonia or a primary amine to give a ring-opened tertiary alcohol 3. For the synthesis of the compounds of this invention where R⁸═H, the diamino alcohol 3 is cyclized to a cyanoguanadine 4 using diphenyl cyanocarbonimidate or dimethyl cyanodithioimidocarbonate typically in refluxing alcohol. Finally, the alcohol functionality of 4 is reacted with a base, for example, sodium hydride, and an alkyl halide to give compound 6. For the synthesis of the compounds of the invention where R⁸=alkyl, the diamino alcohol 3 is first reacted with an alkyl halide and base to give a diaminoether 5. The diaminoether 5 is then cyclized using diphenyl cyanocarbonimidate or dimethyl cyanodithioimidocarbonate as before to give compound 6. The cyano functionality in turn can be hydrolyzed to the corresponding amide using, for example, aqueous acid or base to afford compound 7. For an example of an acid catalyzed hydrolysis, see [Adams, P.; et al.; J. Org. Chem., 1952, 17, 1162].

[0181] Another method for preparing the diaminoether as well as a method for its conversion to N-alkoxy and N-hydroxyguanadines is shown in Scheme 2. The trityl-protected trifluoromethyl ketone 8 is treated with dimethylsulfoxonium methylide, dimethylsulfonium methylide, or diazomethane to form an epoxide 9. The epoxide 9 is then reacted with sodium azide in tetrahydrofuran to form a ring-opened tertiary alcohol 11. With an alkylating agent alkyl halide and a base the alcohol 11 is first converted to an ether, which is followed by removal of the trityl group under acidic condition and then reduction of the azide functionality to a diaminoether 5 using, for example, lithium aluminum hydride.

[0182] This diaminoether 5 is cyclized with thiophosgene or thiocarbonyldiimdazole to form the cyclic thiourea 12. The thiourea is converted to the corresponding methylthioether 13 with base and iodomethane. Reaction of the thioether with hydroxylamine hydrochloride or an alkoxylamine hydrochloride produces the correspopnding N-alkoxy or N-hydroxyguanidine 14. In the case where R⁸=alkyl, the epoxide 9 is opened with an alkyl amine and the resultant diamine 10 is carried through the same synthetic sequence.

[0183] Alternatively, compounds of the present invention may be prepared as shown in Scheme 3. The trityl-protected amino trifluoromethyl ketone is reacted with nitromethane to form an alkoxide. The alkoxide is quenched with a protecting group like TBS-Cl to provide the corresponding silyl ether. This is converted to the nitro-olefin by heating it in the presence of a base (e.g., K₂CO₃). R² (e.g., butyl) can be attached via grignard addition (e.g., BuMgCl), (R²)₃Al addition (e.g., (cyclopropylethyl)₃Al) or other known methods of addition to nitro-olefins. Reduction of the

[0184] nitro group to an amine followed by deprotection of the aniline amine produces the diaminoether which can be transformed to the corresponding N-cyanoguanidine, N-amidoguanadine, or N-methoxy or N-hydroxyguanadine using techniques depicted in Schemes 1 and 2.

[0185] Scheme 4 describes a means of obtaining an amino-ketone useful in the previous schemes. After iodination of an appropriate aniline, the trifluoromethyl group can be introduced using a strong base and ethyl trifluoroacetate.

[0186] Because certain benzo-substituents are incompatible with the methods of the previous schemes, it may be necessary to protect these groups before forming the desired product. In Scheme 5 there is shown a means of obtaining carbonyl-substituted iodo-anilines which can be modified as shown in Scheme 4. After iodination of an acetyl-aniline, the acetyl group is protected by means well known to those of skill in the art, such as using 1,3-propanedithiol. Deprotection of the ketone can then be achieved using HgCl₂ and HgO or other means well known to those of skill in the art.

[0187] In addition to the methods of obtaining keto-anilines described previously, nucleophilic opening of isatoic anhydrides can also be used as shown in Scheme 6. This reaction is accomplished by using an anionic nucleophile of the group R^(1a). See Mack et al, J. Heterocyclic Chem. 1987, 24, 1733-1739; Coppola et al, J. Org. Chem. 1976, 41(6), 825-831; Takimoto et al, Fukuoka Univ. Sci. Reports 1985, 15(1), 37-38; Kadin et al, Synthesis 1977, 500-501; Staiger et al, J. Org. Chem. 1959, 24, 1214-1219.

[0188] One enantiomer of a compound of Formula I may display superior activity compared with the other. Thus, the following stereochemistries are considered to be a part of the present invention.

[0189] When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Thomas J. Tucker, et al, J. Med. Chem. 1994, 37, 2437-2444. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Mark A. Huffman, et al, J. Org. Chem. 1995, 60, 1590-1594.

[0190] Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

[0191] Abbreviations used in the Examples are defined as follows: “° C.” for degrees Celsius, “d” for doublet, “dd” for doublet of doublets, “eq” for equivalent or equivalents, “g” for gram or grams, “mg” for milligram or milligrams, “mL” for milliliter or milliliters, “H” for hydrogen or hydrogens, “hr” for hour or hours, “m” for multiplet, “M” for molar, “min” for minute or minutes, “MHz” for megahertz, “MS” for mass spectroscopy, “nmr” or “NMR” for nuclear magnetic resonance spectroscopy, “t” for triplet, “TLC” for thin layer chromatography, “ACN” for acetic anhydride, “CDI” for carbonyl diimidazole, “DIEA” for diisopropylethylamine, “DIPEA” for diisopropylethylamine, “DMAP” for dimethylaminopyridine, “DME” for dimethoxyethane, “EDAC” for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, “LAH” for lithium aluminium hydride, “TBAF” for tetrabutylammonium fluoride, “TBS-Cl” for t-butyldimethylsilyl chloride, and “TEA” for triethylamine.

Example 1

[0192] Preparation of Compound 6b: 7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine

[0193] To a solution of dimethylsulfoxonium iodide (7.9 g, 35.8 mmol) in dry DMSO (60 mL) at room temperature was added 95% NaH portion-wise (900 mg, 35.8 mmol). This solution was then added to a solution of amino ketone 1a in 90 mL of dry THF. The reaction mixture was treated immediately with water and was then extracted with EtOAc. The organic phase was dried over MgSO₄, filtered and concentrated in vacuo to provide epoxide 2a in quantitative yield. Epoxide 2a was used without further purification in the next step of the synthetic sequence.

[0194] The epoxide 2a was dissolved in EtOH (50 mL) and was treated with excess 2M ammonia in EtOH. The resulting solution was heated to 45° C. for 2 days. The volatiles were removed in vacuo and the remaining oil was purified using column chromatography (50% EtOAc/hexanes). The diamino alcohol 3a was isolated as a yellow oil (3.3 g, 73%) and was used without further purification.

[0195] A solution 3a (100 mg, 0.39 mmol) and diphenyl cyanocarbonimidate (93 mg, 0.39 mmol)in iPrOH(5 mL)was refluxed for 12 h. The solvent was removed in vacuo. Upon addition of dichloromethane to the remaining oily residue, a precipitate formed. This was collected by filtration to provide 90 mg (75%) of alcohol 6a that was used directly in the next step of the synthesis.

[0196] To a solution of alcohol 6a (250 mg, 0.82 mmol) in dry DMSO (4 mL) was added 95% NaH (41.0 mg, 1.64 mmol). After 15 minutes, (bromomethyl)cyclopropane (0.480 mL, 4.92 mmol) was added. After 15 minutes, another 0.240 mL (2.46 mmol) of (bromomethyl)cyclopropane was added. After another 15 minutes, the reaction mixture was poured into saturated NH₄Cl and was extracted 3 times with EtOAc. The combined organic phases were dried over MgSO₄, filtered and concentrated. The crude product was purified using column chromatography (40% EtOAc/hexanes) to provide the crude cyanoguanadine 6b, which was recrystallized from 2% MeOH/CH₂Cl₂, yielding 35 mg (11%, mp 291-293° C.) of pure 6b.

Example 2

[0197] Preparation of Compound 6c: 7-chloro-2-cyanoimino-5-(cyclobutylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine

[0198] To a solution of alcohol 6a (200 mg, 0.66 mmol) in dry DMSO (4 mL) was added 95% NaH (28 mg, 1.12 mmol). After gas evolution had ceased, (bromomethyl)cyclobutane (0.445 mL, 3.96 mmol) was added. After another 15 minutes, the same amounts of both NaH and (bromomethyl)cyclobutane were added again. This addition was repeated two more times before the reaction mixture was quenched with saturated NH₄Cl. The aqueous phase was extracted one time with EtOAc. The organic phase was dried over MgSO₄, filtered and concentrated, and then the crude product was purified via column chromatography (20% EtOAc/CH₂Cl₂) to provide 55 mg (22%) of the title compound 6c in the form of a white solid (mp 239-241° C.).

Example 3

[0199] Preparation of Compound 6d: 7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-3-ethyl-5-trifluoromethyl-1,3-benzodiazepine

[0200] To the epoxide 2a (5.3 g, 22.4 mmol) was added 23 mL of 2M ethylamine in MeOH. The reaction mixture was stirred at room temperature for 12 h and was then heated to 60° C. for 1 h. The solvent was removed in vacuo and the crude product was purified using column chromatography (20% EtOAc/hexanes), providing 4.8 g (76%) of the alcohol 3b, which was isolated as a thick yellow oil.

[0201] To a solution of alcohol 3b (589 mg, 2.1 mmol) in dry DMSO (15 mL) at room temperature was added 95% NaH (68 mg, 2.7 mmol). After 10 min, (bromomethyl)cyclopropane (0.600 mL, 6.2 mmol) was added. The reaction mixture was stirred for 45 min upon which time it was poured into saturated NH₄Cl and was extracted with EtOAc. The organic phase was dried over MgSO₄, filtered and concentrated. The crude product was purified via column chromatography (40% EtOAc/hexanes) to provide 340 mg (48%) of diamine 5a in the form of a yellow oil.

[0202] A solution of diamine 5a (100 mg, 0.30 mmol) and diphenyl cyanocarbonimidate (71 mg, 0.30 mmol) in iPrOH (6 mL) was refluxed overnight. The solvent was removed in vacuo and the crude product was purified via column chromatography (5% Et₂O/CH₂Cl₂) to provide 25 mg (22%, mp 200-203° C.) of the title compound 6d.

Example 4

[0203] Preparation of Compound 12: 7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine

[0204] The trityl-protected epoxide 9b was prepared according to the method described in Example 1 for the preparation of epoxide 2a using the corresponding tritylated ketone. To a suspension of 9b (7.5 g, 15.6 mmol) in dry DMSO (78 mL) was added NaN₃ (1.2 g, 18.7 mmol). The reaction mixture was stirred at room temperature for 2 h, was diluted with EtOAc, and was then poured into brine. The organic phase was seperated and was washed with water and then again with brine. The organic phase was dried over MgSO₄, filtered and concentrated. Trituration with heptane for 12 h provided 5.5 g (67%) of pure alcohol 11a in the form of a white powder.

[0205] Alcohol 11a (5.5 g, 10.5 mmol) in dry DMSO (50 mL) at room temperature was treated with 95% NaH (530 mg, 21.0 mmol) and then with (bromomethyl)cyclopropane (5.1 mL, 52.5 mmol). After stirring for 30 min, the reaction mixture was poured into saturated NH₄Cl and was extracted once with EtOAc. The organic phase was washed with brine and was then dried over MgSO₄, filtered and concentrated. The product was isolated using column chromatography (10% EtOAc/hexanes), providing 2.64 g (44%) of pure 11b.

[0206] Trityl-protected azide 11b (2.64 g, 4.5 mmol) was dissolved in 1:1 CH₂Cl₂:MeOH (40 mL). To this solution was added 1.32 mL of 6N HCl. After stirring at room temperature for 2 h, the solvent was removed in vacuo. The remaining residue was washed with heptane and was then diluted with EtOAc and extracted once with saturated NaHCO₃. The organic phase was dried over MgSO₄, filtered and concentrated to provide in quantitative yield the desired azido compound 11 c that was used in the next step of the synthesis without further purification.

[0207] To a solution of azide 11c (536 mg, 1.6 mmol) in dry THF (8 mL) at 0° C. was added LAH (1M in THF, 1.76 mmol) dropwise. After 2 h, the reaction was poured into 1N NaOH and was extracted with EtOAc. The organic phase was dried over MgSO₄, filtered, concentrated, and purified via column chromatography (70% EtOAc/hexanes) to provide 176 mg (36%) of the pure diamine 5b.

[0208] A solution of 5b (176 mg, 0.57 mmol) in 3 mL of dry toluene was treated with diisopropylethylamine (0.35 mL, 2.0 mmol) followed by thiophosgene (0.06 mL, 0.74 mmol). After stirring for 1.5 h at room temperature, the reaction mixture was poured into water and was extracted with EtOAc. The organic phase was dried over MgSO₄, filtered, and concentrated, then purified using column chromatography (30% EtOAc/hexanes) to provide 74 mg (37%) of the desired thiourea 12a.

[0209] To a solution of 12a (37 mg, 0.10 mmol) in dry DMF (0.5 mL) at room temperature was added 95% NaH (3 mg, 0.11 mmol). After gas evolution was complete, iodomethane (0.12 mL, 0.2 mmol) was added. The reaction mixture was stirred for 2 h and was then diluted with EtOAc and was extracted with water. The organic phase was dried over MgSO₄, filtered, concentrated, and then purified via column chromatography (10% EtOAc/hexanes) to provide 37 mg (100%) of the desired thioether 13a.

[0210] A mixture of 13a (37 mg, 0.10 mmol), methoxylamine hydrochloride (10 mg, 0.12 mmol) and 1 mL of pyridine was refluxed for 1.5 h. After the mixture had cooled it was poured into water and was extracted with EtOAc. The organic phase was dried over MgSO₄, filtered, concentrated and purified using column chromatography (40% EtOAc/hexanes) to provide 20 mg of 14a on the form of a yellow oil. ¹H NMR (300 MHz, acetone-d6) δ7.50 (d, 1H, J=1.2 Hz), 7.25 (dd, 1H, J=8.7, 2.4 Hz), 7.15 (d, 1H, J=8.7 Hz), 8.89−3.78 (m, 1H), 3.50 (dd, 1 H, J=9.6, 6.6 Hz), 3.41 (s, 3H), 2.95 (dd, 1H, J=9.6, 7.5 Hz), 2.71 (d, 1H, J=9.9 Hz), 1.02−0.86 (m, 1H), 0.48−0.34 (m, 2H), 0.17−0.00 (m, 2H).

Example 5

[0211] Preparation of Compound 14b: 7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-3-ethyl-2-methoxyimino-5-trifluoromethyl-1,3- benzodiazepine

[0212] The title compound was prepared as described in Example 4 using diamine 5a as the starting material, beginning with step 5 of the synthetic sequence. ¹H NMR (300 MHz, CDCl₃) δ7.64 (s, 1H), 7.28−7.21 (m, 1H), 6.82 (d, 1H, J=9.0 Hz), 3.74 (s, 3H)m 3.78−3.62 (m, 2H), 3.46−3.31 (m, 2H), 3.28−3.12 (m, 1H), 3.04 (dd, 1H. J=7.2, 2.4 Hz), 1.19 (t, 3H, J=7.2 Hz), 1.16−0.87 (m, 1 H), 0.61−0.50 (m, 2H), 0.21−0.03 (m, 2H). TABLE 1*

m.p. Ex. # Cp R³ R¹ R² A R⁸ (° C.) 1 6b 7-Cl CF₃ O—CH₂-cycPr NCN H 291-293 2 6c 7-Cl CF₃ O—CH₂-cycBu NCN H 239-241 3 6d 7-Cl CF₃ O—CH₂-cycPr NCN Et 200-203 4 14a 7-Cl CF₃ O—CH₂-cycPr NOMe H — 5 14b 7-Cl CF₃ O—CH₂-cycPr NOMe Et —

[0213] The following table contains representative examples of the present invention. Each entry in the table is intended to be paired with each formulae at the start of the table. For example, entry 1 in Table 2 is intended to be paired with a-nn and a′-nn′. TABLE 2*

a b c d

e f g h

ii j k l

m n o p

q r s t

u v w x

y z aa bb

cc dd ee ff

gg hh ii jj

kk ll mm nn

a′ b′ c′ d′

e′ f′ g′ h′

i′ j′ k′ l′

m′ n′ o′ p′

q′ r′ s′ t′

u′ v′ w′ x′

y′ z′ aa′ bb′

cc′ dd′ ee′ ff′

gg′ hh′ ii′ jj′

kk′ ll′ mm′ nn′

[0214] Entry # W X R² 1. CH CH C≡C-cycPr 2. CH CH C≡C-(1-CH₃-cycPr) 3. CH CH C≡C-iPr 4. CH CH C≡C-nPr 5. CH CH C≡C-Bu 6. CH CH C≡C-iBu 7. CH CH C≡C-tBu 8. CH CH C≡C-Et 9. CH CH C≡C-Me 10. CH CH C≡C-Ph 11. CH CH C≡C-2-Pyridyl 12. CH CH C≡C-3-Pyridyl 13. CH CH C≡C-4-Pyridyl 14. CH CH C≡C-2-furanyl 15. CH CH C≡C-3-furanyl 16. CH CH C≡C-2-thienyl 17. CH CH C≡C-3-thienyl 18. CH CH CH═CH-cycPr 19. CH CH CH═CH-iPr 20. CH CH CH═CH-nPr 21. CH CH CH═CH-Bu 22. CH CH CH═CH-iBu 23. CH CH CH═CH-tBu 24. CH CH CH═CH-Et 25. CH CH CH═CH-Me 26. CH CH CH═CH-Ph 27. CH CH CH═CH-2-Pyridyl 28. CH CH CH═CH-3-Pyridyl 29. CH CH CH═CH-4-Pyridyl 30. CH CH CH═CH-2-furanyl 31. CH CH CH═CH-3-furanyl 32. CH CH CH═CH-2-thienyl 33. CH CH CH═CH-3-thienyl 34. CH CH CH₂CH₂CH₂CH₂CH₃ 35. CH CH CH₂CH₂CH(CH₃)₂ 36. CH CH CH₂CH₂CH₂CH₃ 37. CH CH CH₂CH₂CH₃ 38. CH CH CH₂CH₂-cycPr 39. CH CH CH₂CH₂-(1-CH₃-cycPr) 40. CH CH CH₂CH₂-tBu 41. CH CH CH₂CH₂-cycBu 42. CH CH CH₂CH₂-(1-CH₃-cycBu) 43. CH CH CH₂CH₂-2-Pyridyl 44. CH CH CH₂CH₂-3-Pyridyl 45. CH CH CH₂CH₂-4-Pyridyl 46. CH CH CH₂CH₂-2-furanyl 47. CH CH CH₂CH₂-3-furanyl 48. CH CH CH₂CH₂-2-thienyl 49. CH CH CH₂CH₂-3-thienyl 50. CH CH CH₂C≡C-cycPr 51. CH CH CH₂C≡C-2-furanyl 52. CH CH CH₂CH═CH-cycPr 53. CH CH CH₂CH═CH-2-furanyl 54. CH CH CH═CHCH₂-cycPr 55. CH CH CH═CHCH₂-2-furanyl 56. CH CH OCH₂C═C(CH₃)₂ 57. CH CH E-OCH₂C═CHCH₃ 58. CH CH Z-OCH₂C═CHCH₃ 59. CH CH OCH₂CH₃ 60. CH CH OCH₂CH₂CH₃ 61. CH CH OCH₂C═C(Cl)₂ 62. CH CH OCH₂C═CH₂ 63. CH CH OCH₂C≡CCH₃ 64. CH CH OCH₂CH₂CH₃ 65. CH CH OCH₂-cycPr 66. CH CH OCH₂-(1-CH₃-cycPr) 67. CH CH OCH₂-cycBu 68. CH CH OCH₂-(1-CH₃-cycBu) 69. CH CH OCH₂-Phenyl 70. CH CH OCH₂CH₂-cycPr 71. CH CH OCH₂CH═cycPr 72. CCl CH C≡C-cycPr 73. CCl CH C≡C-(1-CH₃-cycPr) 74. CCl CH C≡C-iPr 75. CCl CH C≡C-nPr 76. CCl CH C≡C-Bu 77. CCl CH C≡C-iBu 78. CCl CH C≡C-tBu 79. CCl CH C≡C-Et 80. CCl CH C≡C-Me 81. CCl CH C≡C-Ph 82. CCl CH C≡C-2-Pyridyl 83. CCl CH C≡C-3-Pyridyl 84. CCl CH C≡C-4-Pyridyl 85. CCl CH C≡C-2-furanyl 86. CCl CH C≡C-3-furanyl 87. CCl CH C≡C-2-thienyl 88. CCl CH C≡C-3-thienyl 89. CCl CH CH═CH-cycPr 90. CCl CH CH═CH-iPr 91. CCl CH CH═CH-nPr 92. CCl CH CH═CH-Bu 93. CCl CH CH═CH-iBu 94. CCl CH CH═CH-tBu 95. CCl CH CH═CH-Et 96. CCl CH CH═CH-Me 97. CCl CH CH═CH-Ph 98. CCl CH CH═CH-2-Pyridyl 99. CCl CH CH═CH-3-Pyridyl 100. CCl CH CH═CH-4-Pyridyl 101. CCl CH CH═CH-2-furanyl 102. CCl CH CH═CH-3-furanyl 103. CCl CH CH═CH-2-thienyl 104. CCl CH CH═CH-3-thienyl 105. CCl CH CH₂CH₂CH₂CH₂CH₃ 106. CCl CH CH₂CH₂CH(CH₃)₂ 107. CCl CH CH₂CH₂CH₂CH₃ 108. CCl CH CH₂CH₂CH₃ 109. CCl CH CH₂CH₂-cycPr 110. CCl CH CH₂CH₂-(1-CH₃-cycPr) 111. CCl CH CH₂CH₂-tBu 112. CCl CH CH₂CH₂-cycBu 113. CCl CH CH₂CH₂-(1-CH₃-cycBu) 114. CCl CH CH₂CH₂-2-Pyridyl 115. CCl CH CH₂CH₂-3-Pyridyl 116. CCl CH CH₂CH₂-4-Pyridyl 117. CCl CH CH₂CH₂-2-furanyl 118. CCl CH CH₂CH₂-3-furanyl 119. CCl CH CH₂CH₂-2-thienyl 120. CCl CH CH₂CH₂-3-thienyl 121. CCl CH CH₂C≡C-cycPr 122. CCl CH CH₂C≡C-2-furanyl 123. CCl CH CH₂CH═CH-cycPr 124. CCl CH CH₂CH═CH-2-furanyl 125. CCl CH CH═CHCH₂-cycPr 126. CCl CH CH═CHCH₂-2-furanyl 127. CCl CH OCH₂C═C(CH₃)₂ 128. CCl CH E-CH₂C═C(CH₃)₂ 129. CCl CH Z-OCH₂C═CHCH₃ 130. CCl CH OCH₂CH₃ 131. CCl CH OCH₂CH₂CH₃ 132. CCl CH OCH₂C═C(Cl)₂ 133. CCl CH OCH₂C═CH₂ 134. CCl CH OCH₂C≡CCH₃ 135. CCl CH OCH₂CH₂CH₃ 136. CCl CH OCH₂-cycPr 137. CCl CH OCH₂-(1-CH₃-cycPr) 138. CCl CH OCH₂-cycBu 139. CCl CH OCH₂-(1-CH₃-cycBu) 140. CCl CH OCH₂-Phenyl 141. CCl CH OCH₂CH₂-cycPr 142. CCl CH OCH₂CH=cycPr 143. CH CCl C≡C-cycPr 144. CH CCl C≡C-(1-CH₃-cycPr) 145. CH CCl C≡C-iPr 146. CH CCl C≡C-nPr 147. CH CCl C≡C-Bu 148. CH CCl C≡C-iBu 149. CH CCl C≡C-tBu 150. CH CCl C≡C-Et 151. CH CCl C≡C-Me 152. CH CCI C≡C-Ph 153. CH CCl C≡C-2-Pyridyl 154. CH CCl C≡C-3-Pyridyl 155. CH CCl C≡C-4-Pyridyl 156. CH CCl C≡C-2-furanyl 157. CH CCI C≡C-3-furanyl 158. CH CCl C≡C-2-thienyl 159. CH CCl C≡C-3-thienyl 160. CH CCl CH═CH-cycPr 161. CH CCl CH═CH-iPr 162. CH CCl CH═CH-nPr 163. CH CCl CH═CH-Bu 164. CH CCl CH═CH-iBu 165. CH CCl CH═CH-tBu 166. CH CCl CH═CH-Et 167. CH CCl CH═CH-Me 168. CH CCl CH═CH-Ph 169. CH CCl CH═CH-2-Pyridyl 170. CH CCl CH═CH-3-Pyridyl 171. CH CCl CH═CH-4-Pyridyl 172. CH CCl CH═CH-2-furanyl 173. CH CCl CH═CH-3-furanyl 174. CH CCl CH═CH-2-thienyl 175. CH CCl CH═CH-3-thienyl 176. CH CCl CH₂CH₂CH₂CH₂CH₃ 177. CH CCl CH₂CH₂CH(CH₃)₂ 178. CH CCl CH₂CH₂CH₂CH₃ 179. CH CCl CH₂CH₂CH₃ 180. CH CCl CH₂CH₂-cycPr 181. CH CCl CH₂CH₂-(1-CH₃-cycPr) 182. CH CCl CH₂CH₂-tBu 183. CH CCl CH₂CH₂-cycBu 184. CH CCl CH₂CH₂-(1-CH₃-cycBu) 185. CH CCl CH₂CH₂-2-Pyridyl 186. CH CCl CH₂CH₂-3-Pyridyl 187. CH CCl CH₂CH₂-4-Pyridyl 188. CH CCl CH₂CH₂-2-furanyl 189. CH CCl CH₂CH₂-3-furanyl 190. CH CCl CH₂CH₂-2-thienyl 191. CH CCl CH₂CH₂-3-thienyl 192. CH CCl CH₂C≡C-cycPr 193. CH CCl CH₂C≡C-2-furanyl 194. CH CCl CH₂CH═CH-cycPr 195. CH CCl CH₂CH═CH-2-furanyl 196. CH CCl CH═CHCH₂-cycPr 197. CH CCl CH═CHCH₂-2-furanyl 198. CH CCl OCH₂C═C(CH₃)₂ 199. CH CCl E-OCH₂C═CHCH₃ 200. CH CCl Z-OCH₂C═CHCH₃ 201. CH CCl OCH₂CH₃ 202. CH CCl OCH₂CH₂CH₃ 203. CH CCl OCH₂C═C(Cl)₂ 204. CH CCl OCH₂C═CH₂ 205. CH CCl OCH₂C═CCH₃ 206. CH CCl OCH₂CH₂CH₃ 207. CH CCl OCH₂-cycPr 208. CH CCl OCH₂-(1-CH₃-cycPr) 209. CH CCl OCH₂-cycBu 210. CH CCl OCH₂-(1-CH₃-cycBu) 211. CH CCl OCH₂-Phenyl 212. CH CCl OCH₂CH₂-cycPr 213. CH CCl OCH₂CH═cycPr 214. CCl CCl C≡C-cycPr 215. CCl CCl C≡C-(1-CH₃-cycPr) 216. CCl CCl C≡C-iPr 217. CCl CCl C≡C-nPr 218. CCl CCl C≡C-Bu 219. CCl CCl C≡C-iBu 220. CCl CCl C≡C-tBu 221. CCl CCl C≡C-Et 222. CCl CCl C≡C-Me 223. CCl CCl C≡C-Ph 224. CCl CCl C≡C-2-Pyridyl 225. CCl CCl C≡C-3-Pyridyl 226. CCl CCl C≡C-4-Pyridyl 227. CCl CCl C≡C-2-furanyl 228. CCl CCl C≡C-3-furanyl 229. CCl CCl C≡C-2-thienyl 230. CCl CCl C≡C-3-thienyl 231. CCl CCl CH═CH-cycPr 232. CCl CCl CH═CH-iPr 233. CCl CCl CH═CH-nPr 234. CCl CCl CH═CH-Bu 235. CCl CCl CH═CH-iBu 236. CCl CCl CH═CH-tBu 237. CCl CCl CH═CH-Et 238. CCl CCl CH═CH-Me 239. CCl CCl CH═CH-Ph 240. CCl CCl CH═CH-2-Pyridyl 241. CCl CCl CH═CH-3-Pyridyl 242. CCl CCl CH═CH-4-Pyridyl 243. CCl CCl CH═CH-2-furanyl 244. CCl CCl CH═CH-3-furanyl 245. CCl CCl CH═CH-2-thienyl 246. CCl CCl CH═CH-3-thienyl 247. CCl CCl CH₂CH₂CH₂CH₂CH₃ 248. CCl CCl CH₂CH₂CH(CH₃)₂ 249. CCl CCl CH₂CH₂CH₂CH₃ 250. CCl CCl CH₂CH₂CH₃ 251. CCl CCl CH₂CH₂-cycPr 252. CCl CCl CH₂CH₂-(1-CH₃-cycPr) 253. CCl CCl CH₂CH₂-tBu 254. CCl CCl CH₂CH₂-cycBu 255. CCl CCl CH₂CH₂-(1-CH₃-cycBu) 256. CCl CCl CH₂CH₂-2-Pyridyl 257. CCl CCl CH₂CH₂-3-Pyridyl 258. CCl CCl CH₂CH₂-4-Pyridyl 259. CCl CCl CH₂CH₂-2-furanyl 260. CCl CCl CH₂CH₂-3-furanyl 261. CCl CCl CH₂CH₂-2-thienyl 262. CCl CCl CH₂CH₂-3-thienyl 263. CCl CCl CH₂C≡C-cycPr 264. CCl CCl CH₂C≡C-2-furanyl 265. CCl CCl CH₂CH═CH-cycPr 266. CCl CCl CH₂CH═CH-2-furanyl 267. CCl CCl CH═CHCH₂-cycPr 268. CCl CCl CH═CHCH₂-2-furanyl 269. CCl CCl OCH₂C═C(CH₃)₂ 270. CCl CCl E-OCH₂C═CHCH₃ 271. CCl CCl Z-OCH₂C═CHCH₃ 272. CCl CCl OCH₂CH₃ 273. CCl CCl OCH₂CH₂CH₃ 274. CCl CCl OCH₂C═C(Cl)₂ 275. CCl CCl OCH₂C═CH₂ 276. CCl CCl OCH₂C≡CCH₃ 277. CCl CCl OCH₂CH₂CH₃ 278. CCl CCl OCH₂-cycPr 279. CCl CCl OCH₂-(1-CH₃-cycPr) 280. CCl CCl OCH₂-cycBu 281. CCl CCl OCH₂-(1-CH₃-cycBu) 282. CCl CCl OCH₂-Phenyl 283. CCl CCl OCH₂CH₂-cycPr 284. CCl CCl OCH₂CH=cycPr 285. CF CH C≡C-cycPr 286. CF CH C≡C-(1-CH₃-cycPr) 287. CF CH C≡C-iPr 288. CF CH C≡C-nPr 289. CF CH C≡C-Bu 290. CF CH C≡C-iBu 291. CF CH C≡C-tBu 292. CF CH C≡C-Et 293. CF CH C≡C-Me 294. CF CH C≡C-Ph 295. CF CH C≡C-2-Pyridyl 296. CF CH C≡C-3-Pyridyl 297. CF CH C≡C-4-Pyridyl 298. CF CH C≡C-2-furanyl 299. CF CH C≡C-3-furanyl 300. CF CH C≡C-2-thienyl 301. CF CH C≡C-3-thienyl 302. CF CH CH═CH-cycPr 303. CF CH CH═CH-iPr 304. CF CH CH═CH-nPr 305. CF CH CH═CH-Bu 306. CF CH CH═CH-iBu 307. CF CH CH═CH-tBu 308. CF CH CH═CH-Et 309. CF CH CH═CH-Me 310. CF CH CH═CH-Ph 311. CF CH CH═CH-2-Pyridyl 312. CF CH CH═CH-3-Pyridyl 313. CF CH CH═CH-4-Pyridyl 314. CF CH CH═CH-2-furanyl 315. CF CH CH═CH-3-furanyl 316. CF CH CH═CH-2-thienyl 317. CF CH CH═CH-3-thienyl 318. CF CH CH₂CH₂CH₂CH₂CH₃ 319. CF CH CH₂CH₂CH(CH₃)₂ 320. CF CH CH₂CH₂CH₂CH₃ 321. CF CH CH₂CH₂CH₃ 322. CF CH CH₂CH₂-cycPr 323. CF CH CH₂CH₂-(1-CH₃-cycPr) 324. CF CH CH₂CH₂-tBu 325. CF CH CH₂CH₂-cycBu 326. CF CH CH₂CH₂-(1-CH₃-cycBu) 327. CF CH CH₂CH₂-2-Pyridyl 328. CF CH CH₂CH₂-3-Pyridyl 329. CF CH CH₂CH₂-4-Pyridyl 330. CF CH CH₂CH₂-2-furanyl 331. CF CH CH₂CH₂-3-furanyl 332. CF CH CH₂CH₂-2-thienyl 333. CF CH CH₂CH₂-3-thienyl 334. CF CH CH₂C≡C-cycPr 335. CF CH CH₂C≡C-2-furanyl 336. CF CH CH₂CH═CH-cycPr 337. CF CH CH₂CH═CH-2-furanyl 338. CF CH CH═CHCH₂-cycPr 339. CF CH CH═CHCH₂-2-furanyl 340. CF CH OCH₂C═C(CH₃)₂ 341. CF CH E-OCH₂C═CHCH₃ 342. CF CH Z-OCH₂C═CHCH₃ 343. CF CH OCH₂CH₃ 344. CF CH OCH₂CH₂CH₃ 345. CF CH OCH₂C═C(Cl)₂ 346. CF CH OCH₂C═CH₂ 347. CF CH OCH₂C≡CCH₃ 348. CF CH OCH₂CH₂CH₃ 349. CF CH OCH₂-cycPr 350. CF CH OCH₂-(1-CH₃-cycPr) 351. CF CH OCH₂-cycBu 352. CF CH OCH₂-(1-CH₃-cycBu) 353. CF CH OCH₂-Phenyl 354. CF CH OCH₂CH₂-cycPr 355. CF CH OCH₂CH=cycPr 356. CH CF C≡C-cycPr 357. CH CF C≡C-(1-CH₃-cycPr) 358. CH CF C≡C-iPr 359. CH CF C≡C-nPr 360. CH CF C≡C-Bu 361. CH CF C≡C-iBu 362. CH CF C≡C-tBu 363. CH CF C≡C-Et 364. CH CF C≡C-Me 365. CH CF C≡C-Ph 366. CH CF C≡C-2-Pyridyl 367. CH CF C≡C-3-Pyridyl 368. CH CF C≡C-4-Pyridyl 369. CH CF C≡C-2-furanyl 370. CH CF C≡C-3-furanyl 371. CH CF C≡C-2-thienyl 372. CH CF C≡C-3-thienyl 373. CH CF CH═CH-cycPr 374. CH CF CH═CH-iPr 375. CH CF CH═CH-nPr 376. CH CF CH═CH-Bu 377. CH CF CH═CH-iBu 378. CH CF CH═CH-tBu 379. CH CF CH═CH-Et 380. CH CF CH═CH-Me 381. CH CF CH═CH-Ph 382. CH CF CH═CH-2-Pyridyl 383. CH CF CH═CH-3-Pyridyl 384. CH CF CH═CH-4-Pyridyl 385. CH CF CH═CH-2-furanyl 386. CH CF CH═CH-3-furanyl 387. CH CF CH═CH-2-thienyl 388. CH CF CH═CH-3-thienyl 389. CH CF CH₂CH₂CH₂CH₂CH₃ 390. CH CF CH₂CH₂CH(CH₃)₂ 391. CH CF CH₂CH₂CH₂CH₃ 392. CH CF CH₂CH₂CH₃ 393. CH CF CH₂CH₂-cycPr 394. CH CF CH₂CH₂-(1-CH₃-cycPr) 395. CH CF CH₂CH₂-tBu 396. CH CF CH₂CH₂-cycBu 397. CH CF CH₂CH₂-(1-CH₃-cycBu) 398. CH CF CH₂CH₂-2-Pyridyl 399. CH CF CH₂CH₂-3-Pyridyl 400. CH CF CH₂CH₂-4-Pyridyl 401. CH CF CH₂CH₂-2-furanyl 402. CH CF CH₂CH₂-3-furanyl 403. CH CF CH₂CH₂-2-thienyl 404. CH CF CH₂CH₂-3-thienyl 405. CH CF CH₂C≡C-cycPr 406. CH CF CH₂C≡C-2-furanyl 407. CH CF CH₂CH═CH-cycPr 408. CH CF CH₂CH═CH-2-furanyl 409. CH CF CH═CHCH₂-cycPr 410. CH CF CH═CHCH₂-2-furanyl 411. CH CF OCH₂C═C(CH₃)₂ 412. CH CF E-OCH₂C═CHCH₃ 413. CH CF Z-OCH₂C═CHCH₃ 414. CH CF OCH₂CH₃ 415. CH CF OCH₂CH₂CH₃ 416. CH CF OCH₂C═C(Cl)₂ 417. CH CF OCH₂C═CH₂ 418. CH CF OCH₂C≡CCH₃ 419. CH CF OCH₂CH₂CH₃ 420. CH CF OCH₂-cycPr 421. CH CF OCH₂-(1-CH₃-cycPr) 422. CH CF OCH₂-cycBu 423. CH CF OCH₂-(1-CH₃-cycBu) 424. CH CF OCH₂-Phenyl 425. CH CF OCH₂CH₂-cycPr 426. CH CF OCH₂CH=cycPr 427. CF CF C≡C-cycPr 428. CF CF C≡C-(1-CH₃-cycPr) 429. CF CF C≡C-iPr 430. CF CF C≡C-nPr 431. CF CF C≡C-Bu 432. CF CF C≡C-iBu 433. CF CF C≡C-tBu 434. CF CF C≡C-Et 435. CF CF C≡C-Me 436. CF CF C≡C-Ph 437. CF CF C≡C-2-Pyridyl 438. CF CF C≡C-3-Pyridyl 439. CF CF C≡C-4-Pyridyl 440. CF CF C≡C-2-furanyl 441. CF CF C≡C-3-furanyl 442. CF CF C≡C-2-thienyl 443. CF CF C≡C-3-thienyl 444. CF CF CH═CH-cycPr 445. CF CF CH═CH-iPr 446. CF CF CH═CH-nPr 447. CF CF CH═CH-Bu 448. CF CF CH═CH-iBu 449. CF CF CH═CH-tBu 450. CF CF CH═CH-Et 451. CF CF CH═CH-Me 452. CF CF CH═CH-Ph 453. CF CF CH═CH-2-Pyridyl 454. CF CF CH═CH-3-Pyridyl 455. CF CF CH═CH-4-Pyridyl 456. CF CF CH═CH-2-furanyl 457. CF CF CH═CH-3-furanyl 458. CF CF CH═CH-2-thienyl 459. CF CF CH═CH-3-thienyl 460. CF CF CH₂CH₂CH₂CH₂CH₃ 461. CF CF CH₂CH₂CH(CH₃)₂ 462. CF CF CH₂CH₂CH₂CH₃ 463. CF CF CH₂CH₂CH₃ 464. CF CF CH₂CH₂-cycPr 465. CF CF CH₂CH₂-(1-CH₃-cycPr) 466. CF CF CH₂CH₂-tBu 467. CF CF CH₂CH₂-cycBu 468. CF CF CH₂CH₂-(1-CH₃-cycBu) 469. CF CF CH₂CH₂-2-Pyridyl 470. CF CF CH₂CH₂-3-Pyridyl 471. CF CF CH₂CH₂-4-Pyridyl 472. CF CF CH₂CH₂-2-furanyl 473. CF CF CH₂CH₂-3-furanyl 474. CF CF CH₂CH₂-2-thienyl 475. CF CF CH₂CH₂-3-thienyl 476. CF CF CH₂C≡C-cycPr 477. CF CF CH₂C≡C-2-furanyl 478. CF CF CH₂CH═CH-cycPr 479. CF CF CH₂CH═CH-2-furanyl 480. CF CF CH═CHCH₂-cycPr 481. CF CF CH═CHCH₂-2-furanyl 482. CF CF OCH₂C═C(CH₃)₂ 483. CF CF E-OCH₂C═CHCH₃ 484. CF CF Z-OCH₂C═CHCH₃ 485. CF CF OCH₂CH₃ 486. CF CF OCH₂CH₂CH₃ 487. CF CF OCH₂C═C(Cl)₂ 488. CF CF OCH₂C═CH₂ 489. CF CF OCH₂C≡CCH₃ 490. CF CF OCH₂CH₂CH₃ 491. CF CF OCH₂-cycPr 492. CF CF OCH₂-(1-CH₃-cycPr) 493. CF CF OCH₂-cycBu 494. CF CF OCH₂-(1-CH₃-cycBu) 495. CF CF OCH₂-Phenyl 496. CF CF OCH₂CH₂-cycPr 497. CF CF OCH₂CH═cycPr 498. CCl CF C≡C-cycPr 499. CCl CF C≡C-(1-CH₃-cycPr) 500. CCl CF C≡C-iPr 501. CCl CF C≡C-nPr 502. CCl CF C≡C-Bu 503. CCl CF C≡C-iBu 504. CCl CF C≡C-tBu 505. CCl CF C≡C-Et 506. CCl CF C≡C-Me 507. CCl CF C≡C-Ph 508. CCl CF C≡C-2-Pyridyl 509. CCl CF C≡C-3-Pyridyl 510. CCl CF C≡C-4-Pyridyl 511. CCl CF C≡C-2-furanyl 512. CCl CF C≡C-3-furanyl 513. CCl CF C≡C-2-thienyl 514. CCl CF C≡C-3-thienyl 515. CCl CF CH═CH-cycPr 516. CCl CF CH═CH-iPr 517. CCl CF CH═CH-nPr 518. CCl CF CH═CH-Bu 519. CCl CF CH═CH-iBu 520. CCl CF CH═CH-tBu 521. CCl CF CH═CH-Et 522. CCl CF CH═CH-Me 523. CCl CF CH═CH-Ph 524. CCl CF CH═CH-2-Pyridyl 525. CCl CF CH═CH-3-Pyridyl 526. CCl CF CH═CH-4-Pyridyl 527. CCl CF CH═CH-2-furanyl 528. CCl CF CH═CH-3-furanyl 529. CCl CF CH═CH-2-thienyl 530. CCl CF CH═CH-3-thienyl 531. CCl CF CH₂CH₂CH₂CH₂CH₃ 532. CCl CF CH₂CH₂CH(CH₃)₂ 533. CCl CF CH₂CH₂CH₂CH₃ 534. CCl CF CH₂CH₂CH₃ 535. CCl CF CH₂CH₂-cycPr 536. CCl CF CH₂CH₂-(1-CH₃-cycPr) 537. CCl CF CH₂CH₂-tBu 538. CCl CF CH₂CH₂-cycBu 539. CCl CF CH₂CH₂-(1-CH₃-cycBu) 540. CCl CF CH₂CH₂-2-Pyridyl 541. CCl CF CH₂CH₂-3-Pyridyl 542. CCl CF CH₂CH₂-4-Pyridyl 543. CCl CF CH₂CH₂-2-furanyl 544. CCl CF CH₂CH₂-3-furanyl 545. CCl CF CH₂CH₂-2-thienyl 546. CCl CF CH₂CH₂-3-thienyl 547. CCl CF CH₂C≡C-cycPr 548. CCl CF CH₂C≡C-2-furanyl 549. CCl CF CH₂CH═CH-cycPr 550. CCl CF CH₂CH═CH-2-furanyl 551. CCl CF CH═CHCH₂-cycPr 552. CCl CF CH═CHCH₂-2-furanyl 553. CCl CF OCH₂C═C(CH₃)₂ 554. CCl CF E-OCH₂C═CHCH₃ 555. CCl CF Z-OCH₂C═CHCH₃ 556. CCl CF OCH₂CH₃ 557. CCl CF OCH₂CH₂CH₃ 558. CCl CF OCH₂C═C(Cl)₂ 559. CCl CF OCH₂C═CH₂ 560. CCl CF OCH₂C≡CCH₃ 561. CCl CF OCH₂CH₂CH₃ 562. CCl CF OCH₂-cycPr 563. CCl CF OCH₂-(1-CH₃-cycPr) 564. CCl CF OCH₂-cycBu 565. CCl CF OCH₂-(1-CH₃-cycBu) 566. CCl CF OCH₂-Phenyl 567. CCl CF OCH₂CH₂-cycPr 568. CCl CF OCH₂CH=cycPr 569. CF CCl C≡C-cycPr 570. CF CCl C≡C-(1-CH₃-cycPr) 571. CF CCl C≡C-iPr 572. CF CCl C≡C-nPr 573. CF CCl C≡C-Bu 574. CF CCl C≡C-iBu 575. CF CCl C≡C-tBu 576. CF CCl C≡C-Et 577. CF CCl C≡C-Me 578. CF CCl C≡C-Ph 579. CF CCl C≡C-2-Pyridyl 580. CF CCl C≡C-3-Pyridyl 581. CF CCl C≡C-4-Pyridyl 582. CF CCl C≡C-2-furanyl 583. CF CCl C≡C-3-furanyl 584. CF CCl C≡C-2-thienyl 585. CF CCl C≡C-3-thienyl 586. CF CCl CH═CH-cycPr 587. CF CCl CH═CH-iPr 588. CF CCl CH═CH-nPr 589. CF CCl CH═CH-Bu 590. CF CCl CH═CH-iBu 591. CF CCl CH═CH-tBu 592. CF CCl CH═CH-Et 593. CF CCl CH═CH-Me 594. CF CCl CH═CH-Ph 595. CF CCl CH═CH-2-Pyridyl 596. CF CCl CH═CH-3-Pyridyl 597. CF CCl CH═CH-4-Pyridyl 598. CF CCl CH═CH-2-furanyl 599. CF CCl CH═CH-3-furanyl 600. CF CCl CH═CH-2-thienyl 601. CF CCl CH═CH-3-thienyl 602. CF CCl CH₂CH₂CH₂CH₂CH₃ 603. CF CCl CH₂CH₂CH(CH₃)2 604. CF CCl CH₂CH₂CH₂CH₃ 605. CF CCl CH₂CH₂CH₃ 606. CF CCl CH₂CH₂-cycPr 607. CF CCl CH₂CH₂-(1-CH₃-cycPr) 608. CF CCl CH₂CH₂-tBu 609. CF CCl CH₂CH₂-cycBu 610. CF CCl CH₂CH₂-(1-CH₃-cycBu) 611. CF CCl CH₂CH₂-2-Pyridyl 612. CF CCl CH₂CH₂-3-Pyridyl 613. CF CCl CH₂CH₂-4-Pyridyl 614. CF CCl CH₂CH₂-2-furanyl 615. CF CCl CH₂CH₂-3-furanyl 616. CF CCl CH₂CH₂-2-thienyl 617. CF CCl CH₂CH₂-3-thienyl 618. CF CCl CH₂C≡C-cycPr 619. CF CCl CH₂C≡C-2-furanyl 620. CF CCl CH₂CH═CH-cycPr 621. CF CCl CH₂CH═CH-2-furanyl 622. CF CCl CH═CHCH₂-cycPr 623. CF CCl CH═CHCH₂-2-furanyl 624. CF CCl OCH₂C═C(CH₃)₂ 625. CF CCl E-OCH₂C═CHCH₃ 626. CF CCl Z-OCH₂C═CHCH₃ 627. CF CCl OCH₂CH₃ 628. CF CCl OCH₂CH₂CH₃ 629. CF CCl OCH₂C═C(Cl)₂ 630. CF CCl OCH₂C═CH₂ 631. CF CCl OCH₂C≡CCH₃ 632. CF CCl OCH₂CH₂CH₃ 633. CF CCl OCH₂-cycPr 634. CF CCl OCH₂-(1-CH₃-cycPr) 635. CF CCl OCH₂-cycBu 636. CF CCl OCH₂-(1-CH₃-cycBu) 637. CF CCl OCH₂-Phenyl 638. CF CCl OCH₂CH₂-cycPr 639. CF CCl OCH₂CH=cycPr 640. C(OMe) CH C≡C-cycPr 641. C(OMe) CH C≡C-(1-CH₃-cycPr) 642. C(OMe) CH C≡C-iPr 643. C(OMe) CH C≡C-nPr 644. C(OMe) CH C≡C-Bu 645. C(OMe) CH C≡C-iBu 646. C(OMe) CH C≡C-tBu 647. C(OMe) CH C≡C-Et 648. C(OMe) CH C≡C-Me 649. C(OMe) CH C≡C-Ph 650. C(OMe) CH C≡C-2-Pyridyl 651. C(OMe) CH C≡C-3-Pyridyl 652. C(OMe) CH C≡C-4-Pyridyl 653. C(OMe) CH C≡C-2-furanyl 654. C(OMe) CH C≡C-3-furanyl 655. C(OMe) CH C≡C-2-thienyl 656. C(OMe) CH C≡C-3-thienyl 657. C(OMe) CH CH═CH-cycPr 658. C(OMe) CH CH═CH-iPr 659. C(OMe) CH CH═CH-npr 660. C(OMe) CH CH═CH-Bu 661. C(OMe) CH CH═CH-iBu 662. C(OMe) CH CH═CH-tBu 663. C(OMe) CH CH═CH-Et 664. C(OMe) CH CH═CH-Me 665. C(OMe) CH CH═CH-Ph 666. C(OMe) CH CH═CH-2-Pyridyl 667. C(OMe) CH CH═CH-3-Pyridyl 668. C(OMe) CH CH═CH-4-Pyridyl 669. C(OMe) CH CH═CH-2-furanyl 670. C(OMe) CH CH═CH-3-furanyl 671. C(OMe) CH CH═CH-2-thienyl 672. C(OMe) CH CH═CH-3-thienyl 673. C(OMe) CH CH₂CH₂CH₂CH₂CH₃ 674. C(OMe) CH CH₂CH₂CH(CH₃)₂ 675. C(OMe) CH CH₂CH₂CH₂CH₃ 676. C(OMe) CH CH₂CH₂CH₃ 677. C(OMe) CH CH₂CH₂-cycPr 678. C(OMe) CH CH₂CH₂-(1-CH₃-cycPr) 679. C(OMe) CH CH₂CH₂-tBu 680. C(OMe) CH CH₂CH₂-cycBu 681. C(OMe) CH CH₂CH₂-(1-CH₃-cycBu) 682. C(OMe) CH CH₂CH₂-2-Pyridyl 683. C(OMe) CH CH₂CH₂-3-Pyridyl 684. C(OMe) CH CH₂CH₂-4-Pyridyl 685. C(OMe) CH CH₂CH₂-2-furanyl 686. C(OMe) CH CH₂CH₂-3-furanyl 687. C(OMe) CH CH₂CH₂-2-thienyl 688. C(OMe) CH CH₂CH₂-3-thienyl 689. C(OMe) CH CH₂C≡C-cycPr 690. C(OMe) CH CH₂C≡C-2-furanyl 691. C(OMe) CH CH₂CH═CH-cycPr 692. C(OMe) CH CH₂CH═CH-2-furanyl 693. C(OMe) CH CH═CHCH₂-cycPr 694. C(OMe) CH CH═CHCH₂-2-furanyl 695. C(OMe) CH OCH₂C═C(CH₃)₂ 696. C(OMe) CH E-OCH₂C═CHCH₃ 697. C(OMe) CH Z-OCH₂C═CHCH₃ 698. C(OMe) CH OCH₂CH₃ 699. C(OMe) CH OCH₂CH₂CH₃ 700. C(OMe) CH OCH₂C═C(Cl)₂ 701. C(OMe) CH OCH₂C═CH₂ 702. C(OMe) CH OCH₂C≡CCH₃ 703. C(OMe) CH OCH₂CH₂CH₃ 704. C(OMe) CH OCH₂-cycPr 705. C(OMe) CH OCH₂-(1-CH₃-cycPr) 706. C(OMe) CH OCH₂-cycBu 707. C(OMe) CH OCH₂-(1-CH₃-cycBu) 708. C(OMe) CH OCH₂-Phenyl 709. C(OMe) CH OCH₂CH₂-cycPr 710. C(OMe) CH OCH₂CH═cycPr 711. CH C(OMe) C≡C-cycPr 712. CH C(OMe) C≡C-(1-CH₃-cycPr) 713. CH C(OMe) C≡C-iPr 714. CH C(OMe) C≡C-nPr 715. CH C(OMe) C≡C-Bu 716. CH C(OMe) C≡C-iBu 717. CH C(OMe) C≡C-tBu 718. CH C(OMe) C≡C-Et 719. CH C(OMe) C≡C-Me 720. CH C(OMe) C≡C-Ph 721. CH C(OMe) C≡C-2-Pyridyl 722. CH C(OMe) C≡C-3-Pyridyl 723. CH C(OMe) C≡C-4-Pyridyl 724. CH C(OMe) C≡C-2-furanyl 725. CH C(OMe) C≡C-3-furanyl 726. CH C(OMe) C≡C-2-thienyl 727. CH C(OMe) C≡C-3-thienyl 728. CH C(OMe) CH═CH-cycPr 729. CH C(OMe) CH═CH-iPr 730. CH C(OMe) CH═CH-nPr 731. CH C(OMe) CH═CH-Bu 732. CH C(OMe) CH═CH-iBu 733. CH C(OMe) CH═CH-tBu 734. CH C(OMe) CH═CH-Et 735. CH C(OMe) CH═CH-Me 736. CH C(OMe) CH═CH-Ph 737. CH C(OMe) CH═CH-2-Pyridyl 738. CH C(OMe) CH═CH-3-Pyridyl 739. CH C(OMe) CH═CH-4-Pyridyl 740. CH C(OMe) CH═CH-2-furanyl 741. CH C(OMe) CH═CH-3-furanyl 742. CH C(OMe) CH═CH-2-thienyl 743. CH C(OMe) CH═CH-3-thienyl 744. CH C(OMe) CH₂CH₂CH₂CH₂CH₃ 745. CH C(OMe) CH₂CH₂CH(CH₃)₂ 746. CH C(OMe) CH₂CH₂CH₂CH₃ 747. CH C(OMe) CH₂CH₂CH₃ 748. CH C(OMe) CH₂CH₂-cycPr 749. CH C(OMe) CH₂CH₂-(1-CH₃-cycPr) 750. CH C(OMe) CH₂CH₂-tBu 751. CH C(OMe) CH₂CH₂-cycBu 752. CH C(OMe) CH₂CH₂-(1-CH₃-cycBu) 753. CH C(OMe) CH₂CH₂-2-Pyridyl 754. CH C(OMe) CH₂CH₂-3-Pyridyl 755. CH C(OMe) CH₂CH₂-4-Pyridyl 756. CH C(OMe) CH₂CH₂-2-furanyl 757. CH C(OMe) CH₂CH₂-3-furanyl 758. CH C(OMe) CH₂CH₂-2-thienyl 759. CH C(OMe) CH₂CH₂-3-thienyl 760. CH C(OMe) CH₂C≡C-cycPr 761. CH C(OMe) CH₂C≡C-2-furanyl 762. CH C(OMe) CH₂CH═CH-cycPr 763. CH C(OMe) CH₂CH═CH-2-furanyl 764. CH C(OMe) CH═CHCH₂-cycPr 765. CH C(OMe) CH═CHCH₂-2-furanyl 766. CH C(OMe) OCH₂C═C(CH₃)₂ 767. CH C(OMe) E-OCH₂C═CHCH₃ 768. CH C(OMe) Z-OCH₂C═CHCH₃ 769. CH C(OMe) OCH₂CH₃ 770. CH C(OMe) OCH₂CH₂CH₃ 771. CH C(OMe) OCH₂C═C(Cl)₂ 772. CH C(OMe) OCH₂C═CH₂ 773. CH C(OMe) OCH₂C≡CCH₃ 774. CH C(OMe) OCH₂CH₂CH₃ 775. CH C(OMe) OCH₂-cycPr 776. CH C(OMe) OCH₂-(1-CH₃-cycPr) 777. CH C(OMe) OCH₂-cycBu 778. CH C(OMe) OCH₂-(1-CH₃-cycBu) 779. CH C(OMe) OCH₂-Phenyl 780. CH C(OMe) OCH₂CH₂-cycPr 781. CH C(OMe) OCH₂CH=cycPr 782. —COCH2OC— C≡C-cycPr 783. —COCH2OC— C≡C-(1-CH₃-cycPr) 784. —COCH2OC— C≡C-iPr 785. —COCH2OC— C≡C-nPr 786. —COCH2OC— C≡C-Bu 787. —COCH2OC— C≡C-iBu 788. —COCH2OC— C≡C-tBu 789. —COCH2OC— C≡C-Et 790. —COCH2OC— C≡C-Me 791. —COCH2OC— C≡C-Ph 792. —COCH2OC— C≡C-2-Pyridyl 793. —COCH2OC— C≡C-3-Pyridyl 794. —COCH2OC— C≡C-4-Pyridyl 795. —COCH2OC— C≡C-2-furanyl 796. —COCH2OC— C≡C-3-furanyl 797. —COCH2OC— C≡C-2-thienyl 798. —COCH2OC— C≡C-3-thienyl 799. —COCH2OC— CH═CH-cycPr 800. —COCH2OC— CH═CH-iPr 801. —COCH2OC— CH═CH-nPr 802. —COCH2OC— CH═CH-Bu 803. —COCH2OC— CH═CH-iBu 804. —COCH2OC— CH═CH-tBu 805. —COCH2OC— CH═CH-Et 806. —COCH2OC— CH═CH-Me 807. —COCH2OC— CH═CH-Ph 808. —COCH2OC— CH═CH-2-Pyridyl 809. —COCH2OC— CH═CH-3-Pyridyl 810. —COCH2OC— CH═CH-4-Pyndyl 811. —COCH2OC— CH═CH-2-furanyl 812. —COCH2OC— CH═CH-3-furanyl 813. —COCH2OC— CH═CH-2-thienyl 814. —COCH2OC— CH═CH-3-thienyl 815. —COCH2OC— CH₂CH₂CH₂CH₂CH₃ 816. —COCH2OC— CH₂CH₂CH(CH₃)₂ 817. —COCH2OC— CH₂CH₂CH₂CH₃ 818. —COCH2OC— CH₂CH₂CH₃ 819. —COCH2OC— CH₂CH₂-cycPr 820. —COCH2OC— CH₂CH₂-(1-CH₃-cycPr) 821. —COCH2OC— CH₂CH₂-tBu 822. —COCH2OC— CH₂CH₂-cycBu 823. —COCH2OC— CH₂CH₂-(1-CH₃-cycBu) 824. —COCH2OC— CH₂CH₂-2-Pyridyl 825. —COCH2OC— CH₂CH₂-3-Pyridyl 826. —COCH2OC— CH₂CH₂-4-Pyridyl 827. —COCH2OC— CH₂CH₂-2-furanyl 828. —COCH2OC— CH₂CH₂-3-furanyl 829. —COCH2OC— CH₂CH₂-2-thienyl 830. —COCH2OC— CH₂CH₂-3-thienyl 831. —COCH2OC— CH₂C≡C-cycPr 832. —COCH2OC— CH₂C≡C-2-furanyl 833. —COCH2OC— CH₂CH═CH-cycPr 834. —COCH2OC— CH₂CH═CH-2-furanyl 835. —COCH2OC— CH═CHCH₂-cycPr 836. —COCH2OC— CH═CHCH₂-2-furanyl 837. —COCH2OC— OCH₂C═C(CH₃)₂ 838. —COCH2OC— E-OCH₂C═CHCH₃ 839. —COCH2OC— Z-OCH₂C═CHCH₃ 840. —COCH2OC— OCH₂CH₃ 841. —COCH2OC— OCH₂CH₂CH₃ 842. —COCH2OC— OCH₂C═C(Cl)₂ 843. —COCH2OC— OCH₂C═CH₂ 844. —COCH2OC— OCH₂C≡CCH₃ 845. —COCH2OC— OCH₂CH₂CH₃ 846. —COCH2OC— OCH₂-cycPr 847. —COCH2OC— OCH₂-(1-CH₃-cycPr) 848. —COCH2OC— OCH₂-cycBu 849. —COCH2OC— OCH2-(1-CH₃-cycBu) 850. —COCH2OC— OCH₂-Phenyl 851. —COCH2OC— OCH₂CH₂-cycPr 852. —COCH2OC— OCH₂CH=cycPr

[0215] Utility

[0216] The compounds of this invention possess reverse transcriptase inhibitory activity, in particular, HIV inhibitory efficacy. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are therefore useful as antiviral agents for the treatment of HIV infection and associated diseases. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are effective as inhibitors of HIV growth. The ability of the compounds of the present invention to inhibit viral growth or infectivity is demonstrated in standard assay of viral growth or infectivity, for example, using the assay described below.

[0217] The compounds of formula (I) of the present invention are also useful for the inhibition of HIV in an ex vivo sample containing HIV or expected to be exposed to HIV. Thus, the compounds of the present invention may be used to inhibit HIV present in a body fluid sample (for example, a serum or semen sample) which contains or is suspected to contain or be exposed to HIV.

[0218] The compounds provided by this invention are also useful as standard or reference compounds for use in tests or assays for determining the ability of an agent to inhibit viral clone replication and/or HIV reverse transcriptase, for example in a pharmaceutical research program. Thus, the compounds of the present invention may be used as a control or reference compound in such assays and as a quality control standard. The compounds of the present invention may be provided in a commercial kit or container for use as such standard or reference compound.

[0219] Since the compounds of the present invention exhibit specificity for HIV reverse transcriptase, the compounds of the present invention may also be useful as diagnostic reagents in diagnostic assays for the detection of HIV reverse transcriptase. Thus, inhibition of the reverse transcriptase activity in an assay (such as the assays described herein) by a compound of the present invention would be indicative of the presence of HIV reverse transcriptase and HIV virus.

[0220] As used herein “μg” denotes microgram, “mg” denotes milligram, “g” denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L” denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM” denotes millimolar, “M” denotes molar and “nm” denotes nanometer. “Sigma” stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

[0221] HIV RNA Assay

[0222] DNA Plasmids and in vitro RNA Transcripts:

[0223] Plasmid PDAB 72 containing both gag and pol sequences of BH10 (bp 113-1816) cloned into PTZ 19R was prepared according to Erickson-Viitanen et al. AIDS Research and Human Retroviruses 1989, 5, 577. The plasmid was linearized with Bam HI prior to the generation of in vitro RNA transcripts using the Riboprobe Gemini system II kit (Promega) with T7 RNA polymerase. Synthesized RNA was purified by treatment with RNase free DNAse (Promega), phenol-chloroform extraction, and ethanol precipitation. RNA transcripts were dissolved in water, and stored at −70° C. The concentration of RNA was determined from the A260.

[0224] Probes:

[0225] Biotinylated capture probes were purified by HPLC after synthesis on an Applied Biosystems (Foster City, Calif.) DNA synthesizer by addition of biotin to the 5′ terminal end of the oligonucleotide, using the biotin-phosphoramidite reagent of Cocuzza, Tet. Lett. 1989, 30, 6287. The gag biotinylated capture probe (5-biotin-CTAGCTCCCTGCTTGCCCATACTA 3′) was complementary to nucleotides 889-912 of HXB2 and the pol biotinylated capture probe (5′-biotin-CCCTATCATTTTTGGTTTCCAT 3′ was complementary to nucleotides 2374-2395 of HXB2. Alkaline phosphatase conjugated oligonucleotides used as reporter probes were prepared by Syngene (San Diego, Calif.). The pol reporter probe (5′ CTGTCTTACTTTGATAAAACCTC 3′) was complementary to nucleotides 2403-2425 of HXB2. The gag reporter probe (5′ CCCAGTATTTGTCTACAGCCTTCT 3′) was complementary to nucleotides 950-973 of HXB2. All nucleotide positions are those of the GenBank Genetic Sequence Data Bank as accessed through the Genetics Computer Group Sequence Analysis Software Package (Devereau Nucleic Acids Research 1984, 12, 387). The reporter probes were prepared as 0.5 μM stocks in 2×SSC (0.3 M NaCl, 0.03 M sodium citrate), 0.05 M Tris pH 8.8, 1 mg/mL BSA. The biotinylated capture probes were prepared as 100 μM stocks in water.

[0226] Streptavidin Coated Plates:

[0227] Streptavidin coated plates were obtained from Du Pont Biotechnology Systems (Boston, Mass.).

[0228] Cells and Virus Stocks:

[0229] MT-2 and MT-4 cells were maintained in RPMI 1640 supplemented with 5% fetal calf serum (FCS) for MT-2 cells or 10% FCS for MT-4 cells, 2 mM L-glutamine and 50 μg/mL gentamycin, all from Gibco. HIV-1 RF was propagated in MT-4 cells in the same medium. Virus stocks were prepared approximately 10 days after acute infection of MT-4 cells and stored as aliquots at −70° C. Infectious titers of HIV-l(RF) stocks were 1-3×10⁷ PFU (plaque forming units)/mL as measured by plaque assay on MT-2 cells (see below). Each aliquot of virus stock used for infection was thawed only once.

[0230] For evaluation of antiviral efficacy, cells to be infected were subcultured one day prior to infection. On the day of infection, cells were resuspended at 5×10⁵ cells/mL in RPMI 1640, 5% FCS for bulk infections or at 2×10⁶/mL in Dulbecco's modified Eagles medium with 5% FCS for infection in microtiter plates. Virus was added and culture continued for 3 days at 37° C.

[0231] HIV RNA Assay:

[0232] Cell lysates or purified RNA in 3 M or 5 M GED were mixed with 5 M GED and capture probe to a final guanidinium isothiocyanate concentration of 3 M and a final biotin oligonucleotide concentration of 30 nM. Hybridization was carried out in sealed U bottom 96 well tissue culture plates (Nunc or Costar) for 16-20 hours at 37° C. RNA hybridization reactions were diluted three-fold with deionized water to a final guanidinium isothiocyanate concentration of 1 M and aliquots (150 μL) were transferred to streptavidin coated microtiter plates wells. Binding of capture probe and capture probe-RNA hybrid to the immobilized streptavidin was allowed to proceed for 2 hours at room temperature, after which the plates were washed 6 times with DuPont ELISA plate wash buffer (phosphate buffered saline (PBS), 0.05% Tween 20.) A second hybridization of reporter probe to the immobilized complex of capture probe and hybridized target RNA was carried out in the washed streptavidin coated well by addition of 120 μl of a hybridization cocktail containing 4×SSC, 0.66% Triton×100, 6.66% deionized formamide, 1 mg/mL BSA and 5 nM reporter probe. After hybridization for one hour at 37° C., the plate was again washed 6 times. Immobilized alkaline phosphatase activity was detected by addition of 100 μL of 0.2 mM 4-methylumbelliferyl phosphate (MUBP, JBL Scientific) in buffer δ(2.5 M diethanolamine pH 8.9 (JBL Scientific), 10 mM MgCl₂, 5 mM zinc acetate dihydrate and 5 mM N-hydroxyethyl-ethylene-diamine-triacetic acid). The plates were incubated at 37° C. Fluorescence at 450 nM was measured using a microplate fluorometer (Dynateck) exciting at 365 nM.

[0233] Microplate Based Compound Evaluation in HIV-1 Infected MT-2 Cells:

[0234] Compounds to be evaluated were dissolved in DMSO and diluted in culture medium to twice the highest concentration to be tested and a maximum DMSO concentration of 2%. Further three-fold serial dilutions of the compound in culture medium were performed directly in U bottom microtiter plates (Nunc). After compound dilution, MT-2 cells (50 μL) were added to a final concentration of 5×10⁵ per mL (1×10⁵ per well). Cells were incubated with compounds for 30 minutes at 37° C. in a CO₂ incubator. For evaluation of antiviral potency, an appropriate dilution of HIV-1 (RF) virus stock (50 μL) was added to culture wells containing cells and dilutions of the test compounds. The final volume in each well was 200 μL. Eight wells per plate were left uninfected with 50 μL of medium added in place of virus, while eight wells were infected in the absence of any antiviral compound. For evaluation of compound toxicity, parallel plates were cultured without virus infection.

[0235] After 3 days of culture at 37° C. in a humidified chamber inside a CO₂ incubator, all but 25 μL of medium/well was removed from the HIV infected plates. Thirty seven μL of 5 M GED containing biotinylated capture probe was added to the settled cells and remaining medium in each well to a final concentration of 3 M GED and 30 nM capture probe. Hybridization of the capture probe to HIV RNA in the cell lysate was carried out in the same microplate well used for virus culture by sealing the plate with a plate sealer (Costar), and incubating for 16-20 hrs in a 37° C. incubator. Distilled water was then added to each well to dilute the hybridization reaction three-fold and 150 μL of this diluted mixture was transferred to a streptavidin coated microtiter plate. HIV RNA was quantitated as described above. A standard curve, prepared by adding known amounts of PDAB 72 in vitro RNA transcript to wells containing lysed uninfected cells, was run on each microtiter plate in order to determine the amount of viral RNA made during the infection.

[0236] In order to standardize the virus inoculum used in the evaluation of compounds for antiviral activity, dilutions of virus were selected which resulted in an IC₉₀ value (concentration of compound required to reduce the HIV RNA level by 90%) for dideoxycytidine (ddC) of 0.2 μg/mL. IC₉₀ values of other antiviral compounds, both more and less potent than ddC, were reproducible using several stocks of HIV-1 (RF) when this procedure was followed. This concentration of virus corresponded to ˜3×10⁵ PFU (measured by plaque assay on MT-2 cells) per assay well and typically produced approximately 75% of the maximum viral RNA level achievable at any virus inoculum. For the HIV RNA assay, IC₉₀ values were determined from the percent reduction of net signal (signal from infected cell samples minus signal from uninfected cell samples) in the RNA assay relative to the net signal from infected, untreated cells on the same culture plate (average of eight wells). Valid performance of individual infection and RNA assay tests was judged according to three criteria. It was required that the virus infection should result in an RNA assay signal equal to or greater than the signal generated from 2 ng of PDAB 72 in vitro RNA transcript. The IC₉₀ for ddC, determined in each assay run, should be between 0.1 and 0.3 μg/mL. Finally, the plateau level of viral RNA produced by an effective reverse transcriptase inhibitor should be less than 10% of the level achieved in an uninhibited infection.

[0237] For antiviral potency tests, all manipulations in microtiter plates, following the initial addition of 2× concentrated compound solution to a single row of wells, were performed using a Perkin Elmer/Cetus ProPette.

[0238] Compounds tested in the above assay are considered to be active if they exhibit an IC₉₀ of ≦20 μM. Preferred compounds of the present invention have IC₉₀'s of ≦5 μM. More preferred compounds of the present invention have IC₉₀'s of ≦0.5 μM. Even more preferred compounds of the present invention have IC₉₀'s of ≦0.05 μM. Still more preferred compounds of the present invention have IC₉₀'s of ≦0.005 μM.

[0239] Using the methodology described above, a number of compounds of the present invention were found to exhibit an IC₉₀ of ≦20 μM, thereby confirming the utility of the compounds of the present invention as effective HIV inhibitors.

[0240] Protein Binding and Mutant Resistance

[0241] In order to characterize NNRTI analogs for their clinical efficacy potential the effect of plasma proteins on antiviral potency and measurements of antiviral potency against wild type and mutant variants of HIV which carry amino acid changes in the known binding site for NNRTIs were examined. The rationale for this testing strategy is two fold:

[0242] 1. Many drugs are extensively bound to plasma proteins. Although the binding affinity for most drugs for the major components of human plasma, namely, human serum albumin (HSA) or alpha-1-acid glycoprotein (AAG), is low, these major components are present in high concentration in the blood. Only free or unbound drug is available to cross the infected cell membrane for interaction with the target site (i.e., HIV-1 reverse transcriptase, HIV-1 RT). Therefore, the effect of added HSA+AAG on the antiviral potency in tissue culture more closely reflects the potency of a given compound in the clinical setting. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. The fold increase in apparent IC90 for test compounds in the presence or added levels of HSA and AAG that reflect in vivo concentrations (45 mg/ml HSA, 1 mg/ml AAG) was then calculated. The lower the fold increase, the more compound will be available to interact with the target site.

[0243] 2. The combination of the high rate of virus replication in the infected individual and the poor fidelity of the viral RT results in the production of a quasi-species or mixtures of HIV species in the infected individual. These species will include a majority wild type species, but also mutant variants of HIV and the proportion of a given mutant will reflect its relative fitness and replication rate. Because mutant variants including mutants with changes in the amino acid sequence of the viral RT likely pre-exist in the infected individual's quasi-species, the overall potency observed in the clinical setting will reflect the ability of a drug to inhibit not only wild type HIV-1, but mutant variants as well. We thus have constructed, in a known genetic background, mutant variants of HIV-1 which carry amino acid substitutions at positions thought to be involved in NNRTI binding, and measured the ability of test compounds to inhibit replication of these mutant viruses. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. It is desirable to have a compound which has high activity against a variety of mutants.

[0244] Dosage and Formulation

[0245] The antiviral compounds of this invention can be administered as treatment for viral infections by any means that produces contact of the active agent with the agent's site of action, i.e., the viral reverse transcriptase, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but preferably are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0246] The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to about 1000 milligrams per kilogram of body weight, with the preferred dose being about 0.1 to about 30 mg/kg.

[0247] Dosage forms of compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

[0248] Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

[0249] In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, supra, a standard reference text in this field.

[0250] Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

[0251] Capsules

[0252] A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesium stearic.

[0253] Soft Gelatin Capsules

[0254] A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules should then be washed and dried.

[0255] Tablets

[0256] A large number of tablets can be prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

[0257] Suspension

[0258] An aqueous suspension can be prepared for oral administration so that each 5 mL contain 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mg of vanillin.

[0259] Injectable

[0260] A parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.

[0261] Combination of Components (a) and (b)

[0262] Each therapeutic agent component of this invention can independently be in any dosage form, such as those described above, and can also be administered in various ways, as described above. In the following description component (b) is to be understood to represent one or more agents as described previously. Thus, if components (a) and (b) are to be treated the same or independently, each agent of component (b) may also be treated the same or independently.

[0263] Components (a) and (b) of the present invention may be formulated together, in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a combination product. When component (a) and (b) are not formulated together in a single dosage unit, the component (a) may be administered at the same time as component (b) or in any order; for example component (a) of this invention may be administered first, followed by administration of component (b), or they may be administered in the revserse order. If component (b) contains more that one agent, e.g., one RT inhibitor and one protease inhibitor, these agents may be administered together or in any order. When not administered at the same time, preferably the administration of component (a) and (b) occurs less than about one hour apart. Preferably, the route of administration of component (a) and (b) is oral. The terms oral agent, oral inhibitor, oral compound, or the like, as used herein, denote compounds which may be orally administered. Although it is preferable that component (a) and component (b) both be administered by the same route (that is, for example, both orally) or dosage form, if desired, they may each be administered by different routes (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) or dosage forms.

[0264] As is appreciated by a medical practitioner skilled in the art, the dosage of the combination therapy of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.

[0265] The proper dosage of components (a) and (b) of the present invention will be readily ascertainable by a medical practitioner skilled in the art, based upon the present disclosure. By way of general guidance, typically a daily dosage may be about 100 milligrams to about 1.5 grams of each component. If component (b) represents more than one compound, then typically a daily dosage may be about 100 milligrams to about 1.5 grams of each agent of component (b). By way of general guidance, when the compounds of component (a) and component (b) are administered in combination, the dosage amount of each component may be reduced by about 70-80% relative to the usual dosage of the component when it is administered alone as a single agent for the treatment of HIV infection, in view of the synergistic effect of the combination.

[0266] The combination products of this invention may be formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. In order to minimize contact, for example, where the product is orally administered, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component. In each formulation wherein contact is prevented between components (a) and (b) via a coating or some other material, contact may also be prevented between the individual agents of component (b).

[0267] Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric coated component and the other active ingredient are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer. Optionally, in order to further separate the two layers, one or more placebo layers may be present such that the placebo layer is between the layers of active ingredients. In addition, dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.

[0268] These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time or concurrently by the same manner, will be readily apparent to those skilled in the art, based on the present disclosure.

[0269] Pharmaceutical kits useful for the treatment of HIV infection, which comprise a therapeutically effective amount of a pharmaceutical composition comprising a compound of component (a) and one or more compounds of component (b), in one or more sterile containers, are also within the ambit of the present invention. Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art. Component (a) and component (b) may be in the same sterile container or in separate sterile containers. The sterile containers of materials may comprise separate containers, or one or more multi-part containers, as desired. Component (a) and component (b), may be separate, or physically combined into a single dosage form or unit as described above. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.

[0270] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein. 

What is claimed:
 1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein: A is N—CN, NCONH₂, or N—OR¹¹; W is N or CR³; X is N or CR^(3a); Y is N or CR^(3b); Z is N or CR^(3c); provided that if two of W, X, Y, and Z are N, then the remaining are other than N; R¹ is selected from the group C₁₋₃ alkyl substituted with 0-7 halogen and cyclopropyl; R² is selected from the group —R^(2c), —OR^(2c), —OCHR^(2a)R^(2b), —OCH₂CHR^(2a)R^(2b), —O(CH₂)₂CHR^(2a)R^(2b), —OCHR^(2a)C═C—R^(2b), —OCHR^(2a)C═R^(2c), —OCHR^(2a)C≡C—R^(2b), —SR^(2c), —SCHR^(2a)R^(2b), —SCH₂CHR^(2a)R^(2b), —S(CH₂)₂CHR^(2a)R^(2b), —SCHR^(2a)C═C—R^(2b), —SCHR^(2a)C═R^(2c), —SCHR^(2a)C≡C—R^(2b), —NR^(2a)R^(2c), —NHCHR^(2a)R^(2b), —NHCH₂CHR^(2a)R^(2b), —NH(CH₂)₂CHR^(2a)R^(2b), —NHCHR^(2a)C═C—R^(2b), —NHCHR^(2a)C═R^(2c), and —NHCHR^(2a)C≡C—R^(2b); R^(2a) is selected from the group H, CH₃, CH₂CH₃, CH(CH₃)₂, and CH₂CH₂CH₃; R^(2b) is H or R^(2c); R^(2c) is selected from the group C₁₋₆ alkyl substituted with 0-2 R⁴, C₂₋₅ alkenyl substituted with 0-2 R⁴, C₂₋₅ alkynyl substituted with 0-1 R⁴, C₃₋₆ cycloalkyl substituted with 0-2 R^(3d), phenyl substituted with 0-2 R^(3d), and 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R^(3d); alternatively, the group —NR^(2a)R^(2c) represents a 4-7 membered cyclic amine, wherein 0-1 carbon atoms are replaced by O or NR⁵; R³ is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, —SO₂NR⁵R^(5a), and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S; R^(3a) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, —SO₂NR⁵R^(5a), and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S; alternatively, R³ and R^(3a) together form —OCH₂O—; R^(3b) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)pR⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); alternatively, R^(3a) and R^(3b) together form —OCH₂O—; R^(3c) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); alternatively, R^(3b) and R^(3c) together form —OCH₂O—; R^(3d), at each occurrence, is independently selected from the group C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); R^(3e), at each occurrence, is independently selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); R^(3f), at each occurrence, is independently selected from the group C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); R^(3g), at each occurrence, is independently selected from the group C₁₋₄ alkyl, C₂₋₅ alkenyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, —SO₂NR⁵R^(5a), C₃₋₁₀ carbocycle substituted with 0-3 R^(3f) and a 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-3 R^(3f); and, R⁴ is selected from the group F, Cl, Br, I, C₁₋₆ alkyl substituted with 0-2 R^(3e), C₃₋₁₀ carbocycle substituted with 0-2 R^(3e), phenyl substituted with 0-5 R^(3e), and a 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R^(3e); R⁵ and R^(5a) at each occurrence are independently selected from the group H and C₁₋₄ alkyl; alternatively, R⁵ and R^(5a), together with the nitrogen to which they are attached, combine to form a 5-6 membered ring containing 0-1 O or N atoms; R⁶ is selected from the group H, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, and NR⁵R^(5a); R⁷ is selected from the group C₁₋₃ alkyl and C₁₋₃ alkoxy; R⁸ is selected from the group H, OR⁹, SR⁹, NR⁵R⁹, C₁₋₆ alkyl substituted with 0-3 R^(3g), C₂₋₆ alkenyl substituted with 0-3 R^(3g), C₂₋₆ alkynyl substituted with 0-3 R^(3g), C₃₋₅ cycloalkyl substituted with 0-2 R^(3f), phenyl substituted with 0-5 R^(3f), and a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R^(3f); R⁹ is selected from the group C₃₋₁₀ carbocycle substituted with 0-5 R^(3f) and a 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R^(3f); R¹⁰ is selected from the group C₁₋₄ alkyl and phenyl; and R¹¹ is selected from the group H and C₁₋₄ alkyl
 2. A compound according to claim 1, wherein: R¹ is selected from the group C₁₋₃ alkyl substituted with 1-7 halogen and cyclopropyl; R² is selected from the group —R^(2c), —OR^(2c), OCHR^(2a)R^(2b), —OCH₂CHR^(2a)R^(2b), —O(CH₂)₂CHR^(2a)R^(2b), —OCHR^(2a)C═C—R^(2b), —OCHR^(2a)C═R^(2c), —OCHR^(2a)C≡C—R^(2b), —SR^(2c), —SCHR^(2a)R^(2b), —SCH₂CHR^(2a)R^(2b), —S(CH₂)₂CHR^(2a)R^(2b), SCHR^(2a)C═C—R^(2b), —SCHR^(2a)C═R^(2c), and —SCHR^(2a)C≡C—R^(2b); R^(2a) is selected from the group H, CH₃, CH₂CH₃, CH(CH₃)₂, and CH₂CH₂CH₃; R^(2b) is H or R^(2c); R^(2c) is selected from the group C₁₋₅ alkyl substituted with 0-2 R⁴, C₂₋₅ alkenyl substituted with 0-2 R⁴, C₂₋₅ alkynyl substituted with 0-1 R⁴, C₃₋₆ cycloalkyl substituted with 0-2 R^(3d), and phenyl substituted with 0-2 R^(3d); R³, at each occurrence, is independently selected from the group H, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, NHC(O)NR⁵R^(5a), and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S; R^(3a), at each occurrence, is independently selected from the group H, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, NHC(O)NR⁵R^(5a), and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S; alternatively, R³ and R^(3a) together form —OCH₂O—; R^(3b), at each occurrence, is independently selected from the group H, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a); alternatively, R^(3a) and R^(3b) together form —OCH₂O—; R⁴ is selected from the group Cl, F, C₁₋₄ alkyl substituted with 0-2 R^(3e), C₃₋₅ carbocycle substituted with 0-2 R^(3e), phenyl substituted with 0-5 R^(3e), and a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R^(3e); R⁵ and R^(5a) are independently selected from the group H, CH₃ and C₂H₅; R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a); R⁷ is selected from the group CH₃, C₂H₅, CH(CH₃)₂, OCH₃, OC₂H₅, and OCH(CH₃)₂; and, R⁸ is selected from the group H, cyclopropyl, CH₃, C₂H₅, and CH(CH₃)₂.
 3. A compound according to claim 2, wherein: R¹ is selected from the group CF₃, C₂F₅, and cyclopropyl; R² is selected from the group —R^(2c), —OR^(2c), —OCHR^(2a)R^(2b), —OCH₂CHR^(2a)R^(2b), —OCHR^(2a)C═C—R^(2b), —OCHR^(2a)C═R^(2c), —OCHR^(2a)C≡C—R^(2b), —SR^(2c), —SCHR^(2a)R^(2b), —SCH₂CHR^(2a)R^(2b), SCHR^(2a)C═C—R^(2b), SCHR^(2a)C═R^(2c), and —SCHR^(2a)C≡C—R^(2b); R^(2a) is selected from the group H, CH₃, CH₂CH₃, CH(CH₃)₂, and CH₂CH₂CH₃; R^(2b) is H or R^(2c); R^(2c) is selected from the group C₁₋₃ alkyl substituted with 0-2 R⁴, C₂₋₃ alkenyl substituted with 0-2 R⁴, C₂₋₃ alkynyl substituted with 0-1 R⁴, and C₃₋₆ cycloalkyl substituted with 0-2 R^(3d); R³, at each occurrence, is independently selected from the group H, C₁₋₃ alkyl, OH, C₁₋₃ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a); alternatively, R³ and R^(3a) together form —OCH₂O—; R^(3b) is H; R^(3c) is H; R^(3e), at each occurrence, is independently selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, —NR⁵R^(5a), —C(O)R⁶, and —SO₂NR⁵R^(5a); R⁴ is selected from the group Cl, F, C₁₋₄ alkyl substituted with 0-1 R^(3e), C₃₋₅ carbocycle substituted with 0-2 R^(3e), phenyl substituted with 0-2 R^(3e), and a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R^(3e); R⁵ and R^(5a) are independently selected from the group H, CH₃ and C₂H₅; R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a); R⁷ is selected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅; and, R⁸ is selected from the group H, cyclopropyl, CH₃, and C₂H₅.
 4. A compound according to claim 3, wherein: R¹ is CF₃; R² is selected from the group —R^(2c), —OR^(2c), —OCH₂R^(2b), —OCH₂CH₂R^(2b), —OCH₂C═C—R^(2b), —OCH₂C≡C—R^(2b), —SR^(2c), —SCH₂R^(2b), —SCH₂CH₂R^(2b), —SCH₂C═C—R^(2b), and —SCH₂C≡C—R^(2b); R^(2b) is H or R^(2c); R^(2c) is selected from the group methyl substituted with 0-2 R⁴, ethyl substituted with 0-2 R⁴, propyl substituted with 0-2 R⁴, ethenyl substituted with 0-2 R⁴, 1-propenyl substituted with 0-2 R⁴, 2-propenyl substituted with 0-2 R⁴, ethynyl substituted with 0-2 R⁴, 1-propynyl substituted with 0-2 R⁴, 2-propynyl substituted with 0-2 R⁴, and cyclopropyl substituted with 0-1 R^(3d); R³, at each occurrence, is independently selected from the group H, C₁₋₃ alkyl, OH, C₁₋₃ alkoxy, F, Cl, NR⁵R^(5a), NO₂, —CN, and C(O)R⁶; alternatively, R³ and R^(3a) together form —OCH₂O—; R^(3d), at each occurrence, is independently selected from the group CH, —OH, OCH, OCF₃, F, Cl, and —NR⁵R^(5a); R^(3e), at each occurrence, is independently selected from the group CH₃, —OH, OCH₃, OCF₃, F, Cl, and —NR⁵R^(5a); R⁴ is selected from the group Cl, F, CH₃, CH₂CH₃, cyclopropyl substituted with 0-1 R^(3e), 1-methyl-cyclopropyl substituted with 0-1 R^(3e), cyclobutyl substituted with 0-1 R^(3e), phenyl substituted with 0-2 R^(3e), and a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R^(3e), wherein the heterocyclic group is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, and 2-imidazolyl; R⁵ and R^(5a) are independently selected from the group H, CH₃ and C₂H₅; R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a); R⁷ is selected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅; and, R⁸ is selected from the group H, cyclopropyl, and C₂H₅.
 5. A compound according to claim 4, wherein the compound is of formula Ia


6. A compound according to claim 4, wherein the compound is of formula Ib:


7. A compound according to claim 1, wherein the compound is selected from the group: 7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine; 7-chloro-2-cyanoimino-5-(cyclobutylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine; 7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-3-ethyl-5-trifluoromethyl-1,3-benzodiazepine; 7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine; 7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-3-ethyl-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine; or a pharmaceutically acceptable salt form thereof.
 8. A compound according to claim 1, wherein the compound is selected from the group: (S)-7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine; (S)-7-chloro-2-cyanoimino-5-(cyclobutylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine; (S)-7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-3-ethyl-5-trifluoromethyl-1,3-benzodiazepine; (S)-7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine; (S)-7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-3-ethyl-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine; or a pharmaceutically acceptable salt form thereof.
 9. A compound according to claim 1, wherein the compound is selected from the group: (R) -7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine; (R)-7-chloro-2-cyanoimino-5-(cyclobutylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine; (R)-7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-3-ethyl-5-trifluoromethyl-1,3-benzodiazepine; (R)-7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine; (R)-7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-3-ethyl-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine; or a pharmaceutically acceptable salt form thereof.
 10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or pharmaceutically acceptable salt form thereof.
 11. A method of treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound according to claim 1 or pharmaceutically acceptable salt form thereof.
 12. A method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of: (a) a compound according to claim 1; and, (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
 13. A method according to claim 12, wherein the reverse transcriptase inhibitor is selected from the group AZT, ddC, ddI, d4T, 3TC, DPC082, DPC083, DPC_(961,) DPC_(963,) AG1549 delavirdine, efavirenz, nevirapine, Ro 18,893, trovirdine, MKC-442, HBY 097, ACT, UC-781, UC-782, RD4-2025, and MEN 10979, and the protease inhibitor is selected from the group saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, palinavir, BMS-232623, GS3333, KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, and ABT-378.
 14. A method according to claim 13, wherein the reverse transcriptase inhibitor is selected from the group AZT, efavirenz, and 3TC and the protease inhibitor is selected from the group saquinavir, ritonavir, nelfinavir, and indinavir.
 15. A method according to claim 14 wherein the reverse transcriptase inhibitor is AZT.
 16. A method according to claim 14, wherein the protease inhibitor is indinavir.
 17. A pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of: (a) a compound according to claim 1 or a pharmaceutically acceptable salt form thereof; and, (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers. 